VACCINE  THERAPY 


OPSONIC  METHOD  OF  TREATMENT 


^VACCINE  THERAPY-"'? 


AND 


THE     OPSONIC     METHOD     OF 
TREATMENT 


A    SHORT     COMPENDIUM     FOR     GENERAL 
PRACTITIONERS,  STUDENTS,  AND  OTHERS 


»*  V    '  BY 

A/     V 

F£  W.  ALLEN,  M.D.,  B.S.  (LOND.) 

LATE   PATHOLOGIST   TO   THE    ROYAL    EYE   HOSPITAL  ;    LATE   GULI.   STUDKNT   OF    PATHOLOGY 
GUY'S    HOSPITAL 


SECOND  EDITION 


PHILADELPHIA 

P.   BLAKISTON'S  SON  &  CO. 

1012    WALNUT    STREET 
1908 


(D  1O 


Printed  in  Erujlund 


THE  very  kind  reception  accorded  to  the  First  Edition, 
alike  by  critics  and  by  those  for  whose  use  it  was  designed, 
has  encouraged  the  production  of  this  Second  Edition. 
My  best  thanks  are  due  to  friends  and  reviewers  who 
pointed  out  several  defects  and  slight  mistakes  ;  these,  I 
trust,  they  will  find  lacking  in  the  present  volume.  As 
regards  certain  views  and  theories  to  which  exception 
was  taken,  adequate  reasons  for  their  revisal  have  not 
been  demonstrated,  and  they  are  retained.  So  great  has 
been  the  progress  of  vaccine  therapy  during  the  past 
year  that  such  enlargement  has  been  necessitated  as 
almost  to  justify  the  present  volume  being  regarded  as 
a  new  book.  So  conclusive  has  been  the  evidence 
adduced  of  the  favourable  influence  of  vaccine  therapy, 
when  employed  by  skilled  hands  in  suitable  cases,  that 
no  longer  is  the  help  of  the  immunizator  being  sought  only 
when  all  other  measures  have  failed  ;  he  is  now  regarded 
as  a  useful  adjuvant  to  such  other  therapeutic  aids  as 
clinical  experience  has  proved  appropriate  ;  and  at  no 
time  has  the  future  of  vaccine  therapy  seemed  so  bright, 
and  its  place  in  practical  surgery  and  medicine  so  assured, 
as  it  does  at  present.  To  my  friend  Mr.  F.  L.  Armitage 


vi         PREFACE  TO  THE  SECOND  EDITION 

my  best  thanks  are  due  for  the  use  of  his  very  complete 
list  of  references  to  the  work  done  during  the  past  year, 
and  for  his  help  with  the  manuscript  ;  and,  among  others, 
to  Drs.  Houston,  Wynn,  Stewart,  Benham,  Williamson, 
Captain  Forster,  I.M.S.,  and  Colonel  Semple,  I.M.S.,  for 
reprints  and  other  useful  information. 


58s,  WIMPOLE  STREET,  W. 
September,  1908. 


PREFACE  TO  THE  FIRST  EDITION 

So  prominent  a  place  is  this  method  of  treatment  now 
assuming  in  medical  practice,  and  so  scattered  is  the 
literature  concerning  it,  that  the  time  seemed  ripe  for 
an  endeavour  to  collect  such  facts  as  might  suffice  to  give 
a  general  idea  of  the  subject.  Theories  and  opinions 
have  been  kept  within  as  small  bounds  as  possible,  and 
prominence  given  to  the  results  achieved  in  actual  prac- 
tice. No  pretence  is  made  of  completeness,  but  it  is 
hoped  that  the  great  and  ever-increasing  utility  of  opsonic 
work  may  have  been  adequately  demonstrated.  My 
best  thanks  are  due  to  Dr.  J.  W.  Eyre  for  corrections 
and  suggestions,  and  for  the  loan  of  Charts  XI.  and 
XII.,  and  to  other  friends  for  revision  of  certain  sections. 
Beginners  may  find  it  advantageous  to  defer  the 
reading  of  Chapter  I.  until  the  end. 


58s,  WIMPOLE  STREET,  W. 
November,  1907. 


CONTENTS 

INTRODUCTION 
HISTORY  OF  ORIGIN  OF  VACCINE  THERAPY 

CHAPTER  I 

OPSONINS :  WHAT  THEY  ARE,  THEIR  NATURE 
AND  SOURCE 

PAGES 

The  method  of  demonstrating  the  presence  of  opsonins  in  blood- 
serum — The  nature  and  constitution  of  opsonins — Their  super- 
ficial resemblance  to  ferments — Their  relationship  to  other 
immune  bodies — Specific  and  non-specific  opsonins — Anti- 
opsonins — Site  of  formation  in  the  body — Their  fate  in  the 
organism  -  4 — 16 

CHAPTER  II 
PRINCIPLES  INVOLVED  IN  VACCINE  THERAPY 

Relationship  of  infection  to  opsonic  power  of  the  blood — Effects 
of  injection  of  a  bacterial  vaccine — Negative  and  positive 
phases — Regulation  of  dosage — Other  methods  of  raising  the 
index — Other  considerations  besides  elevation  of  index  17 — 28 

CHAPTER  III 

DETERMINATION  OF  THE  OPSONIC  INDEX 

Definition  of  the  opsonic  index— Method  of  its  determination — 
Its  accuracy  discussed — Other  methods  of  estimating  the 
opsonic  content  of  the  blood  -  ...  29 — 44 


x  CONTEXTS 

CHAPTER  IV 
PREPARATION  OF  THE  VACCINE 

I'AC.KS 

Preparation  of  the  bacterial  vaccine — Isolation  and  cultivation  of 
the  various  organisms — Preparation  of  the  emulsion  ;  its 
standardization,  sterilization  and  tubing — The  various  forms 
of  tuberculin — Preparation  of  combined  vaccines — Method  of 
administration  -  -  -  45 — 70 

CHAPTER  V 

THE  OPSONIC  INDEX  IN  HEALTH  AND  DISEASE :  ITS 
VALUE  IN  DIAGNOSIS,  PROGNOSIS,  AND  TREATMENT 

The  normal  variations  of  index — Effects  of  exercise,  food,  and 
starvation — The  index  in  infancy — The  index  in  disease — 
Effect  of  exercise — Auto-inoculation — Effect  of  menstruation 
— The  index  as  an  aid  to  diagnosis  in  tuberculosis  and  other 
infections — Special  methods  of  employing  it — As  an  aid  to 
prognosis — Its  value  as  a  guide  in  the  therapeutic  production 
of  immunity  -  71 — 95 

CHAPTER  VI 
INFECTIONS  BY  THE  TUBERCLE  BACILLUS 

./Etiology  of  tuberculosis — Methods  of  establishing  a  diagnosis  of 
tubercular  infection — Necessity  for  determination  of  variety 
of  bacillus  at  work — Human  and  bovine  types — Methods  of 
differentiating  the  two — Varieties  of  tuberculin  :  their  pro- 
perties and  actions — Conduct  of  case  (a)  by  opsonic  methods  ; 
(6)  by  clinical  signs — Apyrexial  and  pyrexial  cases — Mixed  in- 
fections— Results  obtained  by  use  of  tuberculin  in  phthisis 
— Comparative  statistics — Results  obtained  in  other  tuber- 
culous infections  -  96 — 149 

CHAPTER  VII 
THE  STAPHYLOCOCCUS 

Acne — Boils  and  carbuncles — Sycosis — Periostitis  and  osteo- 
myelitis— Septicaemia  and  pya?mia — Cases — Dosage  and  time 
for  administration  .....  1,50 — 156 


CONTENTS  xi 

CHAPTER  VIII 
THE  STREPTOCOCCUS 

PAGES 

The  streptococcus  a  large  genus — Varieties — Ulcerative  endo- 
carditis— Septicaemia  and  pyaemia — Erysipelas — Rheuma- 
tism and  chorea — Scarlet  fever  and  other  infections  -  157 — 166 

CHAPTER  IX 
THE  PNEUMOCOCCUS 

The  index  in  pneumonia — Vaccine  therapy  in  acute  pneumonia — 

Unresolved  pneumonia — Empyema — Peritonitis  -     167 — 171 

CHAPTER  X 

THE  GONOCOCCUS 

The  opsonic  index  in  gonococcal  infections,  and  its  utility  in 
diagnosis  and  treatment,  with  cases  and  charts — Urethritis, 
acute  and  chronic  arthritis,  vulvo-vaginitis  -  -  172 — 183 

CHAPTER  XI 

THE   VACCINE   THERAPY   OF   CATARRH,    NASAL    AND 
TRACHEAL,  AND  OF  THE  ACCESSORY  AIR  SINUSES 

The  bacteriology  of  catarrh — Vaccine  therapy  of  catarrh,  with 

illustrative  cases  -  -     184 — 191 

CHAPTER  XII 
THE  COLON,  TYPHOID,  AND  DYSENTERY  GROUPS 

THE  COLON  GROUP:  Illustrative  cases — Cholecystitis — Appendi- 
citis— Endometritis — Puerperal  fever — Cystitis,  etc.  -  192 — 196 

THE  TYPHOID  GROUP  :  Bacillus  typhosus  —  The  paratyphoid 
bacilli — Types  of  fever — Methods  of  diagnosis — Isolation  of 
bacteria  from  blood — Widal's  test — Anti-typhoid  immuniza- 
tion— Preparation  of  anti-typhoid  vaccine — Effects  of  inocu- 
lation— Typhoid  carriers — Treatment  of  enteric  fever  with 
sera  and  vaccines  -  .  -  196 — 202 

THE  DYSENTERY  GROUP  :  Clinical  types  of  bacillary  dysentery — 

Their  vaccine  therapy — Dosage  and  results      -  -     202 — 205 


xii  CONTEXTS 

CHAPTER  XIII 

THE    M1CROCOCCUS   UELITESSIS,    BACILLUS   PARA-^ 
LYTICANS,  MICROCOCCUS  NEOFORMANS,  MEXIN- 
GOCOCCUS,  ACTINOMYCOSIS  206—214 

CHAPTER  XIV 
VACCINE  THERAPY  IN  EYE  DISEASES 

Tuberculous  keratitis,  iritis,  choroiditis — Conjunctivitis  due  to 
tubercle  bacillus,  pneumococcus,  gonococcus,  bacillus  of 
Friedlander,  bacillus  of  Morax-Axenfeld — Corneal  ulcers 
— '  Hordeolum ' — Meibomians — Dacryocystitis  -  215 — 226 

APPENDIX 

Opsonic  index  determinations — Special  points  of  importance  in 
respect  to  certain  bacteria — The  tubercle  bacillus — Special 
methods  for  its  detection  in  sputum,  faeces,  and  urine — 
Cultural  methods — Special  staining  methods  for  human 
and  bovine  varieties  — '  Splitter  ' —  Effect  on  the  index  to 
the  human  strain  of  injections  of  T.R.  of  bovine  origin 
— The  Index  to  both  types  in  certain  cases  of  pulmonary 
phthisis,  with  charts  -  -  227 — 235 

INDEX       -  -        236—244 


VACCINE  THERAPY 

AND  THE 

OPSONIC  METHOD  OF  TKEATMENT 

INTRODUCTION 

IT  was  in  1798  that  Jenner  gave  to  the  world  the  results 
of  his  observations  and  experiments  upon  small-pox  and 
the  production  of  an  artificial  immunity  against  it,  under 
the  title  '  An  Inquiry  into  the  Causes  and  Effects  of  the 
Variola  Vaccinae.' 

Although  we  are  as  yet  ignorant  of  the  cause  of  small- 
pox, and  can  only  conjecture  upon  the  nature  of  vaccina- 
tion, we  have,  from  analogy  with  other  similar  processes, 
reason  for  the  belief  that  it  consists  of  an  active  immuniza- 
tion by  the  agency  of  an  attenuated  form  of  the  causal 
organism. 

In  Jennerian  vaccination  we  find  the  genesis  of  the 
opsonic  form  of  treatment,  and  although  the  two  pro- 
cesses are  really  very  different  in  nature,  the  connection 
is  preserved  in  the  name  '  vaccine,'  somewhat  indis- 
creetly given  to  the  killed  bacterial  emulsions  now  em- 
ployed. The  name  is  certainly  an  ill-chosen  one,  inas- 
much as  the  laity  at  once  think  of  all  the  arguments  of 
the  conscientious  objector,  and  hesitate  about  submitting 
themselves  to  what  they  firmly  believe  to  be  a  process 
identical  with  vaccination. 

1 


2  VACCINE  THERAPY 

Pasteur  carried  on  the  work  initiated  by  Jenner,  and 
endeavoured  in  divers  directions  to  induce  a  prophylaxis 
by  the  inoculation,  mostly  in  an  attenuated  form,  of  the 
bacterial  agents  themselves  or  products  derived  from 
them. 

Koch,  in  1890,  however,  was  the  first  to  attempt  the  cure 
of  an  infection  by  a  specific  remedy — viz.,  of  tuberculosis 
by  means  of  tuberculin.  Unfortunately,  doses  far  in 
excess  of  those  now  employed  were  used,  with  the  result 
that  tuberculin  fell  into  grave  disrepute. 

Denys  and  Leclef  immunized  rabbits  against  strepto- 
cocci, and  showed  that  the  resultant  increased  phago- 
cytosis was  due  not  to  any  changes  in  the  leucocytes, 
but  to  an  alteration  in  the  serum  ;  they  demonstrated  that 
the  leucocytes  of  the  immunized  animal,  when  placed  in 
normal  serum,  showed  no  greater  phagocytic  activity  than 
did  normal  leucocytes. 

The  studies  of  Leishman  on  phagocytosis  paved  the 
way  for  the  discoveries  of  Wright  upon  the  bactericidal 
agents  present  in  the  blood,  and  in  especial  of  the  one  to 
which  he  gave  the  name  of  '  opsonin.'  Having  devised  a 
means  of  accurately  estimating  the  opsonic  content  of 
the  blood,  he  was  thereby  enabled  to  learn  the  reason  of 
the  previous  failures  of  tuberculin,  more  or  less  to  obviate 
the  attendant  danger,  and  place  the  opsonic  method  of 
treatment  of  tuberculosis  upon  a  scientific  basis. 

Pfeiffer  claims  priority  to  Wright  for  the  discovery  of 
the  production  of  immunity  by  the  injection  of  killed 
bacterial  cultures,  while  Neufeld  and  Rimpau  (1904),  in- 
dependently of  Wright,  discovered  that  the  substances 
in  antistreptococcal  and  antipneumococcal  sera  favour- 
ing phagocytosis  united  with  the  bacteria  and  were 
thermostable.  To  Wright,  however,  is  due  the  entire  credit 


INTRODUCTION  3 

of  originating  the  idea  of  estimating  the  changes  in  the 
opsonic  content  of  the  blood  as  guidance  in  the  thera- 
peutic use  of  bacterial  vaccines.  The  seed  he  sowed  has 
flourished  greatly — how  greatly  the  following  pages  will 
briefly  indicate — and  it  would  appear  that  to  the  genesis 
of  a  new,  of  a  scientific,  system  of  medicine  the  impulse 
has  now  been  given.  The  medicine  of  the  future  is 
the  medicine  of  vaccines  and  of  sera.  The  empiricism 
of  the  past  will  give  way  to  methods  based  upon 
scientific  knowledge,  and  the  public  will  no  longer 
look  upon  medicine  with  a  sceptical  eye,  and  dose 
themselves  with  ineffective  nostrums.  The  surgeon 
will  triumph  where  now  he  fails,  and,  armed  with  addi- 
tional power,  he  will  not  fear  the  inroads  of  bacterial 
invasion. 


1—2 


CHAPTER  I 

OPSONINS :   WHAT  THEY  ARE,  THEIR  NATURE 
AND  SOURCE 

OF  the  means  whereby  the  body  tissues  are  enabled  to 
overcome  bacterial  invasion  our  knowledge  is  as  yet  far 
from  perfect.  The  process  is  admittedly  a  very  complex 
one.  Various  substances,  to  which  the  names  '  agglu- 
tinins,'  '  precipitins,'  '  stimulins,'  '  lysins,'  and  '  op- 
sonins,'  are  given,  are  considered  each  to  play  a  part  in 
enabling  the  phagocytic  cells  to  complete  the  destruction 
of  the  infecting  bacteria.  Metchnikoff  holds  that  the 
principal  part  is  played  by  the  substances  to  which  he 
Jias  given  the  name  '  stimulins.'  The  presence  of  these 
in  the  tissue  fluids  he  has  not  yet  succeeded  in  satisfac- 
torily demonstrating,  but  considers  their  function  to  be 
that  of  acting  upon  the  phagocytes  so  as  to  stimulate 
them  to  perform  phagocytosis.  While  not  denying  the 
existence  of  opsonins,  he  assigns  to  them  but  a  secondary 
part.  Wright,  on  the  other  hand,  has  demonstrated 
beyond  doubt  the  presence  in  the  blood  of  substances 
which  act  upon  the  bacteria,  and  get  them  ready  for  the 
completion  of  their  destruction  by  the  phagocytes.  To 
these  bodies  he  has  given  the  name  of  '  opsonins.'  It 
would  appear  possible  for  phagocytosis  to  proceed  with- 
out prior  opsonization  of  the  bacteria,  unless  it  be  argued 
— and  this  seems  very  plausible — that  the  phagocytic  cells 
contain  opsonins  in  their  plasma  fluid  from  which  it  is 

4 


OPSONIN  S  :  WHAT  THEY  ARE  5 

hardly  possible  to  free  them.  Be  this  as  it  may,  it  is 
beyond  question  that  the  presence  of  opsonin  materially 
assists  the  processes  of  phagocytosis. 

The  method  whereby  the  presence  of  opsonin  in  Hood- 
serum  is  demonstrated  is  as  follows  :  A  little  freshly-drawn 
blood  is  immediately  received  into  eight  or  ten  times  its 
volume  of  2  per  cent,  sodium  citrate  to  prevent  coagula- 
tion. The  blood-cells  are  then  thrown  down  by  rapidly 
centrifuging,  and  the  supernatant  liquid  pipetted  off. 
The  cells  are  then  thoroughly  washed  with  a  considerable 
bulk  of  a  solution  of  0-8  per  cent,  sodium  chloride  in  dis- 
tilled water,  and  again  thrown  down  by  means  of  the 
centrifuge,  this  process  being  repeated  two  or  three  times, 
so  that  finally  the  cells  are  washed  practically  free  from 
all  blood-plasma,  and  are  left  suspended  in  a  very  small 
volume  of  the  normal  saline  solution,  as  uniform  a  mixture 
as  possible  being  made.  A  twelve  to  eighteen  hour  old 
culture  on  agar  of  any  organism — say  Staphylococcus 
albus — is  then  taken,  and  a  thick  emulsion  made  with  a 
solution  of  0- 1  per  cent,  sodium  chloride  in  distilled  water. 
Clumps  are  thrown  down  by  means  of  the  centrifuge,  and 
the  bacterial  emulsion  divided  into  two  parts,  A  and  B. 
A  is  set  aside  ;  to  B  an  equal  volume  of  fresh  blood-serum 
is  added,  and  the  two  thoroughly  mixed  together  and 
heated  in  an  incubator  at  37°  C.  for  fifteen  minutes.  The 
bacteria  are  then  thrown  down  by  means  of  the  centrifuge, 
and  as  much  liquid  as  possible  pipetted  off.  The  bacteria 
are  well  washed  with  0-1  per  cent,  solution  of  sodium 
chloride  in  distilled  water,  and  again  thrown  down,  this 
process  being  repeated  several  times.  Finally,  an  emul- 
sion of  the  bacteria  is  made  in  the  salt  solution  exactly 
like  A,  and  the  numbers  present  respectively  in  emulsions 
A  and  B  counted,  the  thicker  emulsion  being  then  diluted 
to  exactly  the  same  strength  as  the  weaker.  We  have 


6  VACCINE  THERAPY 

then  a  suspension  of  blood-cells  of  which  unit  volumes 
contain  the  same  number  of  polymorphonuclear  white 
cells — j'.e..  of  phagocytes — and  two  emulsions  of  the  same 
strength  of  a  given  organism  in  0-1  per  cent,  salt  solution 
differing  only  in  the  fact  that  the  bacteria  in  one  (B) 
have  been  acted  upon  by  blood-serum  at  37°  C.  for 
fifteen  minutes.  If  this  has  had  no  action  upon  the 
organisms,  then  identical  results  should  be  obtained  by 
the  following  procedure  :  Equal  volumes  of  the  blood - 
cells  and  the  bacterial  emulsion  A  are  then  thoroughly 
mixed  together  in  a  capillary  pipette  and  incubated  at 
37°  C.  for  fifteen  minutes,  the  same  being  done  with  the 
substitution  of  emulsion  B  for  A.  Films  are  then  spread, 
stained  by  Irishman's  method,  and  observed  under  a 
T^-inch  oil-immersion  lens.  The  number  of  bacteria 
engorged  by  100  polymorphonuclear  leucocytes  is  then 
counted  upon  each  film.  An  experiment  performed  in 
this  way  gave  the  following  result  : 

Bacterial  Emulsion  Number  of  Cocci  in  100  Polymor- 

employed.  phonuclear  Leucocytes. 

A  10 

B  500 

It  is  thus  obvious  that  some  change  is  produced  in  the 
bacteria  by  the  action  of  the  blood-serum  whereby  phago- 
cytosis is  expedited.  To  the  substance  by  which  this 
change  is  brought  about  Wright  gave  the  name  '  opsonin/ 

THE  NATURE  AND  CONSTITUTION  OF  OPSONINS. 

Until  they  have  been  isolated  and  obtained  in  a  state 
of  purity  it  is  obvious  that  the  exact  constitution  of 
opsonins  cannot  be  determined. 

Certain  observations  render  the  view  probable  that  they 
are  of  a  proteid  nature.  Thus,  Yorke1  filtered  normal 
1  Biochemical  Journal,  vol.  ii.,  June,  1907,  p.  357. 


OPSONINS  :  WHAT  THEY  ARE  7 

serum  through  a  sterile  Chamberland  candle  under  very 
high  pressure,  and  found  that  the  opsonin  passed  readily 
through  for  the  first  few  minutes,  but  that  after  that  only 
traces  permeated  the  candle-wall,  owing  to  the  pores  being 
filled  up  by  the  proteids  of  the  serum.  The  residue  in  the 
filter,  beside  containing  comparatively  unaltered  serum 
consisted  also  of  a  gelatinous  substance,  adherent  to  the 
sides  of  the  candle  and  of  high  opsonic  power.  It  would 
thus  appear  that  opsonins  will  not  pass  through  a 
Chamberland  candle  the  pores  of  which  have  been  blocked 
up  with  gelatine  or  proteid  substance.  They  would  there- 
fore appear  to  be  of  a  '  colloidal  '  nature.  Lamar  and 
Bispham1  showed  also  that  they  were  not  dialysable,  and 
that  they  are  carried  down  with  the  euglobin  when  serum 
is  half  saturated  with  ammonium  sulphate. 

In  certain  respects  they  bear  some  resemblance  to  the 
ferments.  Thus,  serum  can  be  diluted  to  a  considerable 
extent  without  marked  lessening  of  its  opsonic  power. 
Noguchi2  has  also  shown  that  they  are  not  destroyed  by 
drying  the  serum  at  23°  C.,  and  that  in  this  desiccated  state 
they  retain  their  activity  after  two  years,  and  are,  more- 
over, comparatively  resistant  to  heat.  Exposure  to  a  tem- 
perature of  120°  C.  but  slightly  impairs  their  power,  which 
is  not  altogether  destroyed  by  a  temperature  of  150°  C. 

Like  ferments,  opsonins  are  also  very  sensitive  to  slight 
alterations  in  the  acidity  or  alkalinity  of  the  medium  in 
which  they  are  dissolved,  displaying  the  greatest  activity 
in  a  solution  of  neutral  reaction.  As  regards  their 
biological  constitution  diverse  views  are  held.  It  would, 
however,  appear  that  the  opsonins  present  in  normal 
serum  and  in  that  of  an  infected  or  immunized  animal, 
which  is  known  as  an  '  immune  '  serum,  are  not  quite  the 

1  Journal  of  Experimental  Medicine,  December,  1906. 

2  Ibid.,  vol.  ix.,  No.  4,  p.  455. 


8  VACCINE  THERAPY 

same  thing,  and  the  elucidation  of  this  question  has  been 
much  hindered  by  the  failure,  especially  of  the  earlier 
investigators,  to  recognize  this  possibility. 

The  following  experiment  of  Yorke  and  Smith1  upon 
normal  serum  corrected  earlier  observations  by  Bulloch 
and  Western,  and  has  been  amply  confirmed  by  other 
investigators.  A  strong  emulsion  was  made  of  anthrax 
bacilli  in  0-9  per  cent.  NaCl  solution,  and  killed  by  heating 
at  100°  C.  for  thirty  minutes.  The  bacilli  were  then 
thrown  down  by  centrifuge,  and  washed  thrice  with 
0-9  per  cent.  NaCl  solution.  The  washed  dead  bacteria 
were  then  made  up  into  a  strong  emulsion,  and  added  to 
two  equal  portions  of  '  normal '  serum,  A  and  B.  A  was 
incubated  at  37°  C.  for  thirty  minutes,  B  for  sixty  minutes. 

The  bacteria  were  then  thrown  down,  and  the  super- 
natant sera  tested  for  opsonin  with  staphylococcus  and 
anthrax.  The  control  sera  were  diluted  to  an  equal  extent 
with  0-9  per  cent.  NaCl  solution  and  incubated  for  similar 
times  with  the  like  organismal  emulsions.  The  figures 
obtained  from  the  films  prepared  were  as  follows  : 

TABLE  I. 

Number  of  Bacteria 
phagocytosed  by  Index. 

50  Leucocytes. 

A. — 1.  ANTHRAX  : 

Control  serum    . .          . .       40       . .          . .       1-00 
Treated  serum   . .          . .         8       . .          . .       0-20 

II.  STAPHYLOCOCCUS  : 

Control  serum    . .  . .  341  . .  . .  1-00 

Treated  serum   . .  . .  87  . .  . .  0-25 
B. — I.  ANTHRAX  : 

Control  serum    . .  . .  48  . .  . .  1-00 

Treated  serum   . .  . .  2  . .  . .  0-04 

II.  STAPHYLOCOCCUS  : 

Control  serum    . .          . .     395       . .          . .        1-00 
Treated  serum   ..          ..       70       ..          ..       0-17 

1  Biochemical  Journal,  vol.  li.,  December  19,  1906. 


OPSONINS  :  WHAT  THEY  ARE  9 

Other  experiments  gave  similar  results,  which  have  been 
confirmed  by  Simon,  Potter,  and  others.  It  therefore 
appears  that  the  incubation  of  a  large  number  of  any 
organism  with  serum  will  not  only  greatly  reduce  the 
contained  opsonin  for  that  given  bacterium,  but  those  for 
other  organisms  as  well.  In  other  words,  much  the 
greater  proportion  of  the  opsonin  present  in  '  normal  ' 
serum  is  '  non-specific.'  As  to  how  much  of  the  remaining 
proportion  of  the  opsonin  is  '  specific,'  exact  observations 
are  lacking. 

Numerous  experiments  have  been  performed  which 
demonstrate  a  difference  in  the  behaviour  of  the  opsonins 
of  '  normal '  and  '  immune  '  sera.  Thus,  Bulloch  and 
Western  repeatedly  tested  the  serum  of  human  beings 
against  both  staphylococcus  and  the  tubercle  bacillus. 
Injections  of  tuberculin  were  then  given,  and  found  to 
produce  a  rise  in  the  tuberculo-bpsonin,  while  not  affecting 
the  staphylococcic  opsonin.  Injections  of  killed  staphy- 
lococci  had  the  reverse  effect. 

The  fact,  too,  that  infected  patients  are  found  to  have 
either  a  high  or  a  low  index  towards  that  particular 
organism,  and  a  normal  index  towards  all  others,  points 
to  an  alteration  in  the  opsonin  produced  by  the  in- 
fection. That  this  has  resulted  in  the  production  of  a 
'  specific  '  opsonin  is  rendered  probable  by  numerous 
observations,  of  which  the  following  may  be  given  as  an 
example  : 

If  two  sera,  A  and  B,  be  taken,  A  being  a  '  normal  ' 
serum,  B  that  of  a  person  infected  by  the  tubercle  bacillus 
—i.e.,  an  '  immune  serum ' — and  each  of  these  sera  be 
'divided  into  two  portions,  the  one  of  which  is  heated  at 
60°  C.  for  half  an  hour,  the  other  not,  and  the  opsonizing 
power  of  these  four  specimens  of  serum  towards  the 


10 


tubercle  bacillus  be  estimated,  a  result  like  that  set  out 
in  the  following  table  will  be  obtained  : 


NORMAL 

SKIIUM. 

IMMI'XK 

SEIIVM. 

Unheated 
Portion. 

Heated 
Portion. 

Unheated 
Portion. 

Heated 
Portiou. 

Bacteria  in  100  leuco- 
cytes       

300 

15 

200 

80 

Whereby  it  is  seen  that  the  effect  of  heating  the  serum 
has  been  very  different  in  the  cases  of  the  '  normal  '  and 
'  immune  '  sera  respectively.  In  other  words,  the  amount 
of  '  thermostable  '  opsonin  for  the  tubercle  bacillus  is  much 
greater  in  the  '  immune  '  than  in  the  '  normal '  serum. 

A  comparison  of  the  opsonizing  powers  towards  staphy- 
lococcus  in  the  case  of  these  sera  would  reveal  no  difference 
in  behaviour. 

It  is  therefore  probable  that,  as  a  result  of  the  tuber- 
cular infection,  the  amount  of  '  specific  '  thermostable 
opsonin  has  been  increased. 

To  sum  up,  while  it  must  be  admitted  that  the  demon- 
stration of  '  specificity '  of  opsonins  even  in  '  immune  ' 
sera  is  not  complete,  it  is  yet  highly  probable  that  in  the 
blood-serum  of  a  perfectly  healthy  individual  there  is  a 
minimal  amount  of  opsonin  specific  against  the  various 
pathogenic  bacteria,  while  much  the  greater  proportion  is 
non-specific.  The  suggestion  has  been  made  that  opsonin 
does  not  so  exist  in  blood  or  tissue  plasma  as  such,  but 
as  '  opsinogen,'  needing  contact  with  bacteria  or  other 
substances  for  the  formation  of  '  opsonin,'  just  as 
'  fibrin  '  exists  in  the  blood  as  fibrinogen,  needing  calcium 
salts  for  its  conversion  into  fibrin.  In  an  individual 
infected  by  a  given  bacterium  the  amount  of  opsonin 


OPSONINS  :  WHAT  THEY  ARE  11 

specific  against  that  bacterium  undergoes  considerable 
variation  from  the  normal,  and  is  probably  increased  in 
every  case,  not  necessarily  beyond  the  amount  of  '  specific' 
opsonin  which  the  healthy  individual  is  capable  of  elabo- 
rating, but  beyond  the  amount  which  he  actually  does 
normally  elaborate.  Assuming  that  among  the  other 
protective  mechanisms  of  the  body  a  quantity  '  A  ' 
of  '  specific  '  opsonin  is  necessary  to  enable  a  given 
individual  to  overcome  an  infection  by  a  certain 
bacterium,  his  capacity  for  elaborating  this  specific 
opsonin  '  A  '  may  be  in  excess,  exactly  adequate,  or  in 
default.  In  the  first  and  second  instance  the  infection 
will  be  overcome  in  a  time  varying,  inter  alia,  with  the 
amount  of  specific  opsonin  elaborated.  In  the  last 
instance  it  will  not  be  overcome  until  such  time  as  his 
capacity  is  raised  to  the  necessary  point,  or  unless  the 
other  defensive  mechanisms  of  the  body  suffice. 

As  regards  the  structure  of  opsonins,   the  following 
possible  views  all  have  their  advocates — 

1.  That    opsonins    are    identical  with    certain    other 
immune  bodies. 

(1)  Ambocepters  (Savtchenko). 

(2)  Complements  (Levaditi,  Inmann). 

2.  That  opsonins  are  not  identical  with  these  other 
bodies,  but — 

(1)  Have  a  simple  structure  like  toxins,   agglutinins, 
precipitins,  amboceptors,  complements  ;  or — 

(2)  Have  a  double  structure,  like  cytotoxins  and  hsemo- 
lysins,  needing  the  co-operation  of  a  thermostable,  ambo- 
ceptor-like   body,    and    a   thermolabile  complement-like 
body  (Muir  and  Martin,  Dean,  Cowie,  and  Chapin,  etc.). 

3.  That  opsonins  are  unlike  any  other  antibody,  and 
form  a  class  by  themselves  (as  originally  upheld  by  Wright 


12  VACCINE  THERAPY 

and  Douglas,  Bulloch  and  Atkin,  Keith,  Hektoen,  Neufeld, 
and  others). 

To  enter  into  a  full  discussion  of  all  these  possibilities 
is  quite  outside  the  scope  of  this  book ;  the  theory  ren- 
dered most  probable  by  the  weight  of  present  evidence  is 
the  second  of  these,  which  may  be  enunciated  as  follows  : 
Opsonic  action  is  the  effect  of  two  bodies  acting  together 
— one,  thermostable  and  of  amboceptor-like  nature,  is  the 
essential  substance  ;  alone,  it  is  perhaps  capable  of  op- 
sonizing,  but  its  activity  is  greatly  increased  by  the 
presence  of  a  thermolabile,  complement-like  body.  The 
amboceptor-like  constituent  is  present  only  in  very  small 
quantity  in  normal  serum  ;  hence  the  apparent  thermola- 
bility  of  the  opsonin  in  normal  serum,  whereas  in  an 
'  immune  '  serum  the  amboceptor  plays  the  predominant 
part ;  and  though  heating  results  in  a  loss  of  activity, 
this  is  only  partial.  In  the  case  of  both  normal  and 
immune  serum  this  loss  is  due  to  the  destruction  of  the 
complement-like  constituent.  Considerable  support  is 
lent  to.  this  view  by  recent  experiments,  and  notably  those 
of  Cowie  and  Chapin,1  whereby  they  showed — 

1.  That  heated  normal  serum  may  be  reactivated  by 
the  addition  of  small  amounts  of  fresh  normal  serum,  a 
phagocytosis  resulting  which  is  greater  than  the  sum  of 
the  phagocytoses  of  the  sera  taken  separately.    A  similar 
result  is  obtained  with  heated  '  immune  '  serum — i.e.,  the 
addition  of  complement  in  the  fresh  serum  assists  the 
amboceptors  of  the  heated  serum. 

2.  That  just  as  ordinary  amboceptors  can  effect  com- 
binations at  the  freezing-point,  while  complements  cannot, 
so  with  opsonins.     Thus,   normal  serum  may  have  its 

1  Journal  of  Medical  Research,  October,  1907,  and  February.  1908, 
p.  57  and  p.  95. 


OPSONINS  :  WHAT  THEY  ARE  13 

opsonic  power  for  staphylococcus  removed  by  addition  of 
sufficient  staphylococci,  the  mixture  being  maintained  at 
a  temperature  near  0°  C.  throughout. 

That  this  has  resulted  in  the  binding  of  the  amboceptor- 
like  constituent  while  the  complement  remains  free  is 
shown  by  the  fact  that  serum  so  treated — the  bacteria  with 
bound  amboceptor  having  been  removed  by  centrifuge — 
may  still  have  the  power  to  reactivate  a  heated  serum. 

3.  Bacteria  so  treated — i.e.,  bound  to  amboceptor — if 
thoroughly  washed  with  cold  salt  solution  to  remove 
adherent  complement,  are  not  much  more  susceptible  to 
phagocytosis  by  blood-cells,  washed  free  from  complement, 
than  they  were  before  ;  but  the  addition  to  the  mixture 
of  complement,  either  in  a  little  dilute  normal  serum  or 
in  serum  inactivated  by  contact  with  bacteria  in  the  cold, 
results  in  a  phagocytosis  greatly  above  the  normal. 

4.  Staphylococci    so   treated — i.e.,  bound  with  ambo- 
ceptor— are  much  more  easily  opsonized  by  dilute  normal 
serum,  or  by  serum  which  has  been  inactivated  by  contact 
with  staphylococci  in  the  cold,  than  are  the  same  bacteria 
not  so  treated. 

5.  That  a  heated  serum  loses  its  power  to  be  reacti- 
vated if  previously  treated  with  a  sufficient  number  of 
staphylococci — i.e.,  if  it  has  its  amboceptors  thus  removed. 

Further  support  is  lent  to  this  view  by  the  fact,  pointed 
out  by  Muir  and  Martin  (1906  and  1907),  that  in  the  case 
of  the  thermolabile  constituent  of  normal  serum  various 
substances  which  absorb  complement  also  absorb  opsonin 
— viz.,  erythrocytes,  bacilli,  and  serum — when  combined 
with  their  corresponding  antibodies — viz.,  hsemolytic  and 
bacteriolytic  amboceptors  and  precipitins  respectively — 
whereas  these  substances  have  little  or  no  effect  upon  the 
thermostable  constituent  of  an  immune  serum. 


14 


VACCINE  THERAPY 


ANTI-OPSONINS  :  SPECIFIC  AND  NON-SPECIFIC. 
Hektoen  and  Ruediger1  have  shown  that  many  sub- 
stances, such  as  calcium  and  barium  chlorides,  sodium 
bicarbonate,  lactic  acid,  and  alcohol  have  the  power  of 
inducing  a  marked  general  fall  in  the  opsonic  power  of 
the  blood -serum.  The  addition  of  any  alkali  has  the  same 
effect  as  has  that  of  any  acid  after  the  alkaline  reaction 
of  the  serum  has  been  reduced  past  the  point  of  neutrality. 
These  substances  would  therefore  appear  to  be  non- 
specific anti-opsonins.  Upon  the  other  hand,  if  a 
healthy  man  be  injected  with  antitetanic  serum,  a  specific 
rise  in  the  tetano-opsonic  index  first  occurs.  This  is 
followed,  however,  by  a  general  fall.  Thus,  the  staphylo- 
coccal,  tuberculo-,  and  tetano-opsonic  indices  all  fall 
below  normal  (Yorke  and  Smith2).  A  similar,  though  less 
marked,  general  depression  is  observed  after  injection  of 
antistreptococcal  or  antidiphtheritic  serum.  R.  Brad- 
shaw3  has  recorded  the  following  observations  upon  the 
effect  of  injections  of  antidiphtheritic  serum  upon  the 
tuberculo-opsonic  index. 


No. 

of  Case. 
1 
1 
2 
2 
3 
3 
4 
5 
6 
7 
8 
9 


TABLE  II. 

Interval  since  Anti- 
diphtheritic  Serum  given. 

2  days 
5 

12 
25 
27 
41 
25 
26 
26 
27 
28 

3  months 


Index. 

1-30 
064 
102 
035 
089 
072 
064 
0-72 
062 
0-77 
069 
047 


1  Journal  of  American  Medical  Association,  May,  1906. 

2  Biochemical  Journal,  1906,  p.  341. 

3  Lancet,  May  19,  1906,  p.  1387. 


OPSONINS  :  WHAT  THEY  ARE  15 

Other  observers  do  not,  however,  altogether  agree  with 
these  observations  of  Bradshaw,  but  find  that  the  initial 
fall  does  not  usually  last  nearly  so  long  as  is  indicated 
above,  and  is  followed  by  a  pronounced  subsequent  rise. 
So  much  is  this  the  case  that  marked  improvement  is 
claimed  to  have  been  observed  in  tubercular  subjects  to 
whom  antidiphtheritic  serum  has  been  administered. 

The  experiments  of  Hektoen  and  Ruediger  (supra) 
confirm  the  conclusion  that  the  injection  of  these  sera 
results  in  the  formation  of  specific  anti-opsonins. 

SITE  OF  FORMATION  OF  OPSONINS. 

That  opsonin  is  not  formed  in  the  blood  is  practically 
certain.  The  amount  of  opsonin  present  in  the  blood 
bears  no  definite  relation  soever  to  leucocytosis,  nor  is  it 
affected  by  disease  of  the  blood-forming  organs.  Evi- 
dence is  forthcoming  that  it  is  a  product  of  muscular  or 
subcutaneous  activity.  Allen  has  shown  both  in  man  and 
animals  that  if  limbs  be  thoroughly  perfused  with  normal 
salt  solution  to  remove  all  blood,  and  the  muscles  cooled 
and  minced  and  their  plasma  extracted  in  the  usual 
manner,  that  the  index  of  this  plasma,  despite  slight  dilu- 
tion with  the  saline  solution  used  in  the  perfusion,  is 
markedly  higher  than  that  of  the  blood-serum  towards 
various  organisms.  In  the  instance  of  an  amputated 
leg  the  index  of  the  muscle-plasma  compared  with  that  of 
the  patient's  serum  was  1-4  towards  the  bacillus  of  Fried- 
lander,  the  tubercle  bacillus,  and  Staphylococcus  aureus. 
In  another  case  it  was  found  to  be  1'3. 

The  only  possible  conclusion  is  that  actual  formation 
of  opsonin  occurs  in  the  muscle  tissues,  and  passes  thence 
into  the  blood.  This  explains  the  experience  of  Wright1 
1  Lancet,  August  24,  1907,  p.  494. 


16  VACCTXE  THERAPY 

that  a  certain  case  of  tubercular  ulceration  which  had 
previously  defied  treatment  did  well  when  the  tuberculin 
was  injected  in  a  concentric  manner  around  the  area  of 
ulceration. 

FATE  OF  OPSONINS  IN  THE  ORGANISM. 

As  regards  this  question  but  little  is  known.  It,  how- 
ever, appears  that  all  exudates  and  secretions  contain 
certain  amounts  of  opsonin.  Lawson1  finds  that  it  is 
contained  in  appreciable  amount  in  the  sweat,  and  to  a 
larger  degree  in  the  urine,  and  that  this  excreted  opsonin 
is  increased  during  a  negative  phase  consequent  upon 
the  injection  of  a  bacterial  vaccine.  Milk  also  contains 
opsonin,  perhaps  to  the  extent  of  a  quarter  or  a  fifth  of 
that  of  the  blood,  so  that  the  question  as  to  whether  the 
opsonin  of  the  mother's  milk  can  be  absorbed  through  the 
alimentary  tract  of  the  infant  attains  considerable  im- 
portance. Wells,2  from  a  study  of  the  indices  of  breast- 
fed and  artificially-fed  infants,  has  concluded  that  no 
advantages  in  this  respect  are  possessed  by  the  former 
over  the  latter. 

1  Lancet,  September  7,  1907,  p.  704. 

2  Practitioner,  May,  1908.  p.  635. 


CHAPTER  II 

PEINCIPLES  INVOLVED  IN  VACCINE  THERAPY 

THE  RELATIONSHIP  OF  INFECTION  TO  THE  OPSONIC 
INDEX. 

WHETHER  fall  of  index  be  antecedent  to,  or  the  result  of, 
infection  it  is  as  yet  impossible  to  say,  but  the  following 
observation  clearly  shows  that  infection  and  lowered 
opsonic  content  of  the  blood  go  hand  in  hand.  A  case  of 
chronic  cold  due  to  Friedlander's  bacillus  that  had  been 
injected  some  time  previously  with  the  corresponding 
vaccine  had  an  index  of  2-  6.  Twelve  hours  later  an  acute 
attack  began  to  come  on  with  sneezing  and  shivery  feeling. 
A  specimen  of  blood  was  taken,  and  the  index  found  to 
have  fallen  to  2-0.  Prompt  treatment  was  adopted  and 
an  injection  of  vaccine  given,  which  stopped  further 
progress  of  the  oncoming  cold. 

That  the  fall  of  index  is  antecedent  to,  and  not  the 
result  of,  infection  is  rendered  highly  probable  by  the 
recent  demonstration,  referred  to  later,  of  the  existence 
of  specific  and  non-specific  anti-opsonins,  often  of  a  simple 
chemical  constitution,  and  by  the  following  considera- 
tion :  Many  people,  otherwise  perfectly  free  from  acne, 
frequently  develop  a  crop  of  pustules  when  suffering 
from  constipation.  Their  resistance — i.e.,  their  opsonk- 
index  to  staphylococcus — is  usually  normal,  but  may  be 
assumed  to  be  so  lowered  by  the  absorption  of  toxins — 

17  2 


18  VACCINE  THERAPY 

t.e.,of  anti-opsonins — from  the  bowel  that  infection  then 
occurs.  Infection  having  occurred,  their  index  may 
remain  low.  in  which  event  the  acne  will  become  chronic, 
or  rise  to,  or  over,  normal,  in  which  case  recovery  soon 
ensues. 

Per  contra,  the  throwing  off  of  an  infection  is  accom- 
panied by  rise  of  index.  An  old  sufferer  from  chronic 
colds,  who  had  been  injected  a  month  previously,  had  an 
index  to  Friedlander's  bacillus  of  1-5.  All  the  symptoms 
of  a  fresh  cold  appeared,  but.  as  the  patient  said,  he  felt 
he  had  the  cold  beaten  from  the  start,  and  little  wonder, 
for  in  twenty-four  hours  the  index  rose  to  5*8.  and  the 
patient  was  perfectly  well. 


EFFECT  UPON  THE  OPSONIC  INDEX  OF  INJECTION  OF  A 
BACTERIAL  VACCINE. 

The  statement  is  usually  made  that  the  result  of  the 
injection  of  a  bacterial  vaccine  upon  the  index  to  that 
organism  of  a  healthy  person  is  very  slight.  Any  subse- 
quent depression  of  the  index  is  stated  to  be  of  a  very 
temporary  character  and  of  only  small  extent,  while  the 
rise  of  index  which  follows  the  return  to  the  normal  is 
also  of  a  limited  and  slight  character.  This  statement  is 
substantially  true  for  the  tubercle  bacillus,  but  does  not 
hold  equally  for  other  organisms,  as  the  following  experi- 
ments will  show  : 

Experiment  I. — An  injection  of  250.000,000  dead 
organisms  of  the  Bacillus  septus  was  given  to  a  healthy 
person  not  infected  by  that  organism,  and  samples  of 
blood  taken  on  injection  and  after  intervals  of  three,  six, 
twelve,  eighteen,  twenty-four,  thirty-six,  forty-eight, 
seventy-two,  and  ninety-six  hours.  The  comparative 


PRINCIPLES  INVOLVED 


19 


opsonizing  powers  of  the  various  sera  towards  the  Bacillus 
septus  were  then  determined  in  the  usual  manner,  with 
the  following  results  : 


Serum   1  on  injection 


TABLE  III. 

882  bacilli  in  200  cells. 


2  after  3  hours  544 


3 

6 

,   885 

4 

12 

,   804 

5 

18 

,   949 

6 

24 

,  1,096 

7 

36 

,  1,000 

8 

48 

,  1,044 

9 

72 

,  1,220 

10 

96 

,  1,248 

Index  =1-00 
0-62 
1-00 
0-91 
1-08 
1-25 
1-15 
1-20 
1-38 
1-39 


Experiment  II. — An  exactly  similar  experiment  was 
done  upon  a  second  healthy  individual,  350,000,000 
organisms  of  the  Micrococcus  catarrhalis  being  injected, 
with  the  following  result  : 

TABLE  IV. 

Serum   1  before  injection    942  cocci  in  200  cells.  Index  =1-00 
2  after  3  hours         722  0-77 


6 

9 

15 

22 
28 


580 

825 

1,125 

1,080 

1,131 


0-62 
0-88 
1-20 
1-15 
1-20 


In  both  of  these  experiments  we  see  a  very  pronounced 
depression  indeed  produced  in  the  index,  in  each  case  to 
the  extent  of  0*4.  The  duration  of  this  depression  was 
short,  it  is  true,  but  no  shorter  than  that  obtained  in  a 
similar  experiment  upon  an  infected  person,  as  is  seen  in — 

Experiment  III. — From  the  tracheal  mucus  and  nasal 
secretion  of  an  individual  who  had  been  suffering  for  a 
fortnight  with  a  very  bad  tracheal  cough  a  practically 
pure  culture  of  the  Micrococcus  catarrhalis  was  isolated, 

2—2 


20 


VACCINE  THERAPY 


and  the  index  found  to  be  0-56.  An  injection  of 
250,000,000  organisms  was  given,  and  the  effect  upon  the 
index  determined  as  follows,  the  index  prior  to  injection 
being  called  unity  : 

TABLE  V. 

Serum  1  before  injection     140  cocci  in  100  cells.  Index  =1-00 
2       4  hours  after     90  0-64 


8 
12 
15 
18 


220 
280 
312 
325 


1-57 
200 
223 
232 


The  chief  difference  is  the  much  more  pronounced  sub- 
sequent elevation  of  index.  To  the  depression  of  the 
index  the  term  '  negative  phase  '  was  given  by  Wright, 
while  the  subsequent  rise  he  called  the  'positive  phase.' 
The  negative  phase  thus  comprises  the  interval  when  the 
index  is  falling,  and  also  that  when  it  is  rising  until  the 
level  at  which  it  stood  prior  to  injection  is  again  attained. 
The  full  rise  having  been  attained,  the  crest  of  the  positive 
phase  may  be  said  to  have  been  reached,  as  at  seventy- 
two  hours  in  Experiment  I.  and  at  fifteen  hours  in  Experi- 
ment II.  (supra).  The  index  remains  practically  steady 
at  this  elevated  level  for  a  time,  which  varies  in  different 
individuals  and  for  different  organisms — it  may  be  for 
hours,  days,  or  even  weeks.  This  may  be  termed  the 
;  positive  phase  plateau.'  It  then  begins  to  fall,  and 
falls  with  a  rapidity  which  also  differs  in  different  cases. 

During  the  period  of  falling  in  the  negative  phase  the 
patient  may  present  marked  clinical  features.  For 
instance,  in  cases  of  acne  a  fresh  crop  of  pustules  usually 
appears  ;  in  cases  of  cold  the  cold  gets  worse  ;  in  tuber- 
cular cases  the  patient  may  feel  restless  and  ill  or  ex- 
perience increased  pain  in  a  joint.  Only  rarely  is  the 


PRINCIPLES  INVOLVED  21 

temperature,  pulse,  or  respiration  markedly  affected. 
Very  soon  indeed  after  the  inception  of  the  rise,  even 
before  the  index  has  reached  the  level  at  which  it  stood 
prior  to  injection,  the  patient  may  begin  to  improve  and 
declare  himself  to  feel  better. 

A  very  marked  instance  of  this  was  afforded  in  the 
case  of  a  severe  gonococcal  conjunctivitis,  in  which  the 
pain,  discharge,  and  chemosis  all  diminished  two  days 
before  the  index  had  reached  the  level  at  which  it  originally 
stood.  The  factor  in  improvement  would,  therefore 
appear  to  be  a  '  rising  '  index. 

It  must,  however,  be  mentioned  that  the  above  is  not 
a  complete  description  of  all  that  occurs  or  may  occur 
after  the  injection  of  a  bacterial  vaccine,  and  other  varia- 
tions may  be  introduced  by  modifications  in  the  dosage. 

Thus,  it  is  probable  that  with  a  medium  dose  the  first 
effect  is  a  very  slight  and  very  transient  fall  indeed  of  the 
index,  due  to  the  immediate  combination  of  the  opsonin 
at  the  site  of  injection  with  anti-opsonin  present  in  the 
vaccine.  To  this  the  body  makes  reaction  by  formation 
of  fresh  opsonin,  with  the  result  that  there  ensues  a  short 
period  of  slightly  raised  index,  and  it  would  appear  that  the 
improvement  sometimes  seen  during  the  supposed  '  nega- 
tive '  phase  is  in  reality  due  to  this  initial  temporary  rise. 

After  this  oscillation  the  true  negative  phase  begins, 
to  be  succeeded  by  the  positive  phase,  though  fresh 
oscillations  may  occur  at  any  period. 

With  minimum  doses  of  a  vaccine,  on  the  other  hand, 
all  oscillations  and  the  negative  phase  itself  may  be  elided, 
and  injection  be  followed  by  an  immediate  rise,  limited 
alike  in  extent  and  duration. 

Buxton1    has    demonstrated   the   following   important 
1  British  Medical  Journal,  November  6,  1907,  p.  1421. 


22  VACCINE  THERAPY 

difference  in  the  behaviour  of  a  normal  and  of  an  immun- 
ized animal  to  infection  :  In  the  former  phagocytosis  is 
weak  and  extracellular  bacteriolysis  strong  ;  as  a  result 
of  these  two  factors  extracellular  destruction  of  bacteria 
is  great,  and  the  consequent  liberation  into  the  circulation 
of  the  bacterial  endotoxins  is  great,  whereby  severe 
reaction  upon  certain  cells,  such  as  those  of  the  nerve 
centres,  is  produced.  In  the  '  immunized  '  animal,  on 
the  contrary,  phagocytosis  is  strong  and  extracellular 
bacteriolysis  weak.  The  destruction  of  the  bacteria, 
therefore,  chiefly  occurs  intracellularly.  and  the  endo- 
toxins are  destroyed  before  these  can  enter  the  general 
circulation,  and  so  reach  the  nerve  centres. 

DURATION  OF  NEGATIVE  PHASE  IN  PHTHISIS. 

Lawson  and  Stewart1  investigated  the  duration  of  the 
negative  phase  in  120  cases  of  phthisis.  Their  results 
were  as  follows  : 

No  negative  phase  in  15  cases. 
Persistent  negative  phase  in  21  cases. 
Negative  phase  lasting — 

1,    2,    3,  4,  5,  6,     7,  8,  9,  10,  11,  12,  13,  14  days, 
in  14,  12,  10,  5,  7,  4,  10,  4,  4,    3,    4,    1,    1,    5  cases. 
Total :  84  cases. 

The  pulse  and  respiration  did  not  appear  to  be  affected 
at  all,  while  the  temperature  showed  no  response  during 
the  negative  phase  in  50  per  cent,  of  cases.  It  would 
thus  appear  that  in  41  per  cent,  of  the  cases  the  negative 
phase  lasted  over  a  week.  Upon  the  yet  more  important 
questions  as  to  the  interval  occupied  in  various  cases  in 
attaining  the  crest  of  the  positive  phase  and  the  duration 
of  the  plateau  published  information  is  lacking. 
1  Lancet,  December  9,  1905,  p.  1682. 


PRINCIPLES  INVOLVED  23 

The  significance  of  a  persistent  negative  phase  after  a 
first  injection  of  tuberculin  is  great.  It  may  mean  that 
the  case  is  one  altogether  unsuited  to  this  course  of  treat- 
ment on  account  of  the  immunizing  machinery  having 
altogether  broken  down  ;  it  may  mean  that  the  initial 
dose  was  much  too  large,  in  which  case  it  is  unnecessary 
to  wait  any  longer  than  until  all  constitutional  symptoms 
have  disappeared  before  reinoculating  at  this  level  with 
a  much  diminished  dose ;  or  it  may  be  merely  a  peculiar 
phenomenon  that  the  author  has  several  times  experienced, 
especially  in  chronic  gonorrhoeal  cases.  As  subsequent 
events  showed,  the  immunizing  machinery  was  far  from 
exhausted,  nor  was  the  dose  too  large,  yet  the  index  fell 
markedly,  and  there  it  remained  for  weeks  at  a  new  low 
level.  The  repetition  of  the  original  dose  resulted  in  a 
perfectly  satisfactory  response,  as  did  all  subsequent 
injections.  In  these  instances,  then,  it  is  probably  good 
practice,  except  in  obviously  bad  cases,  to  repeat  the 
original  dose  a  second  time.  A  further  fall  and  persist- 
ence of  the  negative  phase  would  be  warning  to  wait  a 
few  weeks  and  then  begin  again  with  a  dose  only  a  third 
or  quarter  as  great  as  that  previously  employed.  Yet, 
again,  in  cases  which  have  been  doing  well  and  had  several 
injections  the  usual  dose  will  produce  an  unexpectedly 
long  negative  phase,  lasting  for  three,  four,  or  five  weeks, 
although  the  patient  apparently  continues  to  improve. 
What  this  means  I  know  not  at  all,  but  the  safer  course 
appears  to  be  to  wait  overlong  rather  than  to  get  impatient 
and  inject  prematurely. 


24 


VACCIXE  THERAPY 


THE  CUMULATION  OF  NEGATIVE  AND  OF  POSITIVE  PHASES. 

A  second  injection  during  a  negative  phase  will  result 
in  further  depression  of  the  index  to  yet  a  lower  level — 
that  is,  one  negative  phase  may  be  superimposed  upon 
another.  The  same  holds  true  for  positive  phases,  and 
this  production  of  cumulated  positive  phases  is  the  great 
aim  in  opsonic  treatment,  for  in  this  way  the  index  may 
be  raised  to  a  very  high  level.  It  still  remains  true,  how- 
ever, that  the  first  result  of  an  injection  is  to  produce  a 
negative  phase,  so  that  a  slight  lowering  of  the  raised 
index  at  first  results,  to  be  followed  by  a  further  rise. 
This  cumulation  of  postive  phases  may  be  thus  shown 
diagrammatically  (Chart  I.)  : 


Days  i 


CHART  I. 
78       9      10      II       12      13 


W      15      16      17     18 


Index 

1-4  • 

^^ 

1-2  - 

^^^^x         /^ 

10  - 

/ 

N^/1^ 

0  9 

z 

0-8  f        •        • 

y 

/                                        . 

n.7-. 

O-fi- 

\ 

/ 

; 

0-5- 

\ 

y 

' 

04- 

k. 

/ 

< 

r    1st  Negative  Phase. 

Subsequent  Positive  T       2nd  Negative      7  Part  of  Subse- 
Phase.                                r:..i-t               quent  Positive 

PbBM 

*  =  injection  of  250,000,000  coccL 


It  is  generally  held  that  this  much-to-be-desired  object 
is  unattainable  in  the  case  of  tuberculin  injections  ;  that 
a  cumulation  of  positive  phases  cannot  be  produced,  and 


PRINCIPLES  INVOLVED  25 

that  each  injection  is  to  be  conducted  as  if  a  new  case 
were  being  begun,  except  that  gradually  increasing  doses 
are  to  be  employed.  While  this  is  generally  true,  frequent 
determination  of  the  index  will  sometimes  enable  the 
psychological  moment  to  be  seized,  and  a  cumulation 
of  positive  phases  to  be  produced.  A  few  additional  cases 
seem,  again,  to  be  especially  predisposed  to  such  a 
result. 

In  tubercular  cases,  then,  it  is  customary  to  allow  the 
good  effects  of  one  injection,  produced  by  the  resultant 
positive  phase,  to  take  full  effect  before  again  inoculating. 
This  means,  as  a  rule,  an  interval  of  about  three  weeks 
between  successive  inoculations.  In  other  injections  the 
aim  always  is  to  superimpose  one  positive  phase  upon 
another.  To  this  end  a  fresh  injection  is  given  while  the 
previous  positive  phase  is  still  on,  and  the  best  time  is 
coincident  with  the  attainment  of  the  crest  or  a  day  or 
two  after,  rather  than  when  the  index  has  again  begun 
to  descend. 


REGULATION  OF  DOSAGE. 

That  doses  of  appropriate  magnitude  be  employed  is 
of  importance  secondary  not  even  to  proper  spacing  of 
the  several  inoculations.  Experience  has  shown  that 
the  proper  initial  dose  varies  considerably  for  different 
organisms  and  to  a  less  extent  for  different  persons.  The 
average  initial  dose  for  each  organism  is  given  later.  Let 
us  suppose  that  this  dose  has  been  given  in  a  certain 
instance,  the  index  prior  to  inoculation  having  been 
found  to  be  subnormal.  A  fresh  determination  of  the 
index  is  made  twenty-four  hours  after  injection,  and 
again  seven  or  ten  days  later. 


26  VACCINE  THERAPY 

The  various  possible  results  and  the  deductions  there- 
from may  be  thus  displayed  schematically  : 

Index  24  Hoars  Index  7  or  10  Davs  -^i     , - 

after  Injection.  Later.  Auction. 

Slight  fall.          Further  fall.  Dose  too  large. 

Slight  rise.          But  little  altered.          Dose  too  small. 
Slight  fall.          Marked  rise.  Dose  correct. 

It  will  be  found,  as  treatment  progresses,  that  gradually 
increasing  doses,  often  at  shorter  intervals,  have  to  be 
employed  to  produce  any  marked  effect  upon  the  index. 
Thus,  in  staphylococcal  cases  the  initial  dose  of  250,000,000 
organisms  may  have  finally  to  be  increased  even  to 
5,000,000,000  before  a  cure  is  effected.  So  long  as  a 
certain  dose  produces  an  adequate  response  increase  of  it 
is  not  advisable,  but  so  soon  as  this  result  is  not  achieved 
the  indication  for  doubling  the  dose  is  present.  The 
approaching  termination  of  infection  is  indicated  when 
these  large  doses  finally  fail  to  produce  a  rise  of  more 
than  one  or  two  decimal  points  in  the  index,  which 
assumes  a  level  at  unity  or  slightly  above  it.  One  or 
two  more  large  doses  are  then  to  be  followed  by  diminished 
doses  at  increasing  intervals. 


OTHER  METHODS  OF  RAISING  THE  OPSONIC  INDEX. 

Injections  of  bacterial  vaccine  are  not  the  sole  means 
whereby  the  opsonic  index  may  be  raised.  Applications 
of  heat  and  massage  probably  have  their  good  effect  by 
acting  locally  in  this  manner. 

It  has  been  shown  that  Bier's  treatment  by  passive 
congestion  has  the  effect  of  raising  the  general  opsonic 
power  of  the  blood  to  an  infecting  organism,  while  nuclein 
injected  subcutaneously  and  yeast  by  the  mouth  (Huggard 


PRINCIPLES  INVOLVED  27 

and  Moreland1)  have  a  similar  action.  This  explains  the 
well-known  therapeutic  action  of  yeast  in  erysipelas, 
furunculosis.  and  acne,  and  the  varied  results  obtained 
by  its  administration  uncontrolled  by  the  opsonic  index. 

Maiden2  showed  that  its  action  was  probably  due  to 
the  nucleo-albumins  it  contained. 

It  has  been  already  mentioned  that  the  administration 
of  antidiphtheritic  serum  produces  a  temporary  fall  in 
the  tuberculo-opsonic  index,  which  is  followed  by  a  sub- 
sequent rise. 

Bosanquet  and  French3  studied  the  effect  of  Marmorek's 
antituberculous  serum  upon  the  tuberculo-opsonic  index 
in  five  cases.  They  found  that,  when  given  subcutane- 
ously  in  one  case,  an  alarming  fall  in  the  index  from 
1-05  to  0-25  occurred ;  cessation  of  the  injections  was 
followed  by  a  rapid  rise  to  1-45. 

In  the  other  four  cases  the  rectal  method  of  administra- 
tion was  followed.  In  three  of  these  a  rise  in  the  index 
was  produced,  usually  after  three  or  four  daily  doses  had 
been  given.  A  maximum  index  was  soon  reached,  and 
continued  with  slight  oscillations  for  three  or  four  weeks 
while  the  serum  was  being  given,  and  for  about  a  week 
subsequently.  In  the  fourth  case,  which  was  a  very 
advanced  one,  the  index  fell  from  1-75  to  0-8  during 
treatment,  recovering  subsequently  slowly  to  1-0. 

It  would  thus  appear  probable  that  in  certain  instances 
the  beneficial  results  of  antisera  may  be,  at  all  events, 
partly  due  to  the  elevation  produced  in  the  opsonic  index. 

1  Lancet,  June  3,  1905. 

2  British  Medical  Journal,  July  1,  1905. 

3  Ibid.,  April  13,  1907,  p.  862. 


28  VACCINE  THERAPY 

ELEVATION    OF    THE    OPSOXIC    INDEX    NOT    THE    SOLE 
NECESSITY. 

Wright  has  been  at  especial  pains  to  point  out  that  the 
successful  combat  of  bacterial  invasion  does  not  depend 
upon  elevation  of  the  opsonic  index  alone.  Increase  in 
the  bacteriotropic  substances  of  the  blood  having  been 
secured,  it  still  remains  to  insure  that  these  be  brought 
in  sufficient  amount  to  the  point  of  attack.  Experi- 
ment has  shown  that  the  fluid  portion  of  pus  may  be 
entirely  free  from  opsonin,  while  the  amount  of  the  latter 
in  the  serous  exudates  in  pathological  conditions  of  the 
peritoneum,  meninges,  pleura,  and  pericardium  may  be 
very  greatly  diminished.  It  therefore  becomes  necessary 
to  insure  the  removal  of  the  fluid  poor  in  antibacterial 
substances,  and  its  partial  replacement  by  lymph  rich  in 
such  substances.  This  end  is  secured  in  various  ways,  as 
by  opening  a  fluctuating  abscess,  doing  a  laparotomy  upon 
a  tubercular  peritonitis,  or  tapping  an  empyema.  Other 
cases  there  are,  such  as  more  or  less  non-discharging  sinuses, 
where  dense  granulation  tissue  and  deposits  of  fibrin  pre- 
vent free  access  of  lymph,  and  brawny  swellings  where  the 
same  result  is  brought  about  by  blockage  of  the  lymphatics. 
The  former  of  these  conditions  Wright  meets  by  the  intro- 
duction into  the  sinus  of  a  solution  of  0-  5  per  cent,  citrate  of 
soda  and  5  per  cent,  sodium  chloride,  the  former  decalcify- 
ing the  lymph,  and  so  preventing  its  coagulation,  the  latter 
by  osmosis  causing  transudation  of  fluid  from  the  vessels. 

The  surgeon  has  been  wont  to  secure  a  similar  result 
by  scraping  and  the  application  of  caustics.  Brawny 
swellings  are  to  be  freely  incised,  and  the  coagulability 
of  the  lymph  diminished  by  three-hourly  doses  of  60  grains 
of  sodium  citrate.  Further  consideration  is  given  to  this 
question  in  later  pages. 


CHAPTER  III 

DETERMINATION  OF  THE  OPSONIC  INDEX 

DEFINITION  OF  THE  OPSONIC  INDEX. 
The  opsonic  index  may  be  defined  as  the  ratio  : 

Opsonic  content  of  unit  volume  of  the  patient's  blood-serum 
A  normal  person's 

This  is  now  determined  according  to  a  method  first  intro- 
duced by  Leishman  for  the  estimation  of  the  phagocytic 
power  of  blood.  Other  methods  have  been  employed, 
but  need  not  be  referred  to,  as  they  have  been  completely 
superseded  by  Wright's  modification  of  the  above. 
The  following  materials  and  apparatus  are  required  : 

1.  A  sufficient  quantity  of  the  patient's  blood-serum 
and  of  that  of  the  normal  person. 

2.  Blood-cells  which  have  been  thoroughly  freed  from 
the  plasma  in  which  they  normally  float. 

3.  An  emulsion  of  the  bacterium  towards  which  the 
opsonic  index  of  the  patient  is  to  be  determined. 

4.  Glass-tubing  fV  inch  and  T\  inch  in  external  diameter 
— the  smaller  for  collection  of  the  blood  samples,  the  larger 
for  the  opsonic  determinations.     The  former  are  to  be  cut 
into  lengths  of  about  3  inches,  and  drawn  out  into  capillary 
threads  at  each  end,  which  are  then  cut  off  short.     The 
latter  are  to  be  drawn  out  at  one  end  only  into  fine  capil- 
lary threads  about  6  inches  long  and  as  far  as  possible 
of  uniform  bore. 

29 


30  VACCTXE  THERAPY 

5.  Strong  rubber  teats,  file,  grease  pencil. 

6.  Centrifuge  with  haematocrite  attachment,  and  glass 
tubes  to  fit  the  same. 

7.  Watch-glasses  and  platinum  loop. 

8.  The   following   solutions  in  sterile   distilled  water, 
carefully  freed  from  dust  and  hairs,  not  by  filtering,  but 
by  centrifugalization  : 

(a)  1-5  per  cent,  to  2  per  cent,  neutral  sodium 

citrate. 

(b)  0-8  per  cent,  sodium  chloride. 

(c)  0-1  per  cent,  sodium  chloride. 

9.  Glass  slides  thoroughly  grease-free. 

10.  Incubator    (Hearson's    biological),   maintained    at 
37°  C. 

11.  Methylic  alcohol  for  fixing. 

12.  Appropriate  staining  solutions — viz.,  for  all  organ- 
isms  except   tubercle,    Leishman's   stain ;    for   tubercle, 
carbol   fuchsin,    20   per   cent,    sulphuric    acid,    absolute 
alcohol,  and  toluedene  blue. 

13.  Porcelain  jar  with  metal  cover  for  holding  slides 
during  fixing  and  staining. 

14.  Microscope   with   ^-inch   oil-immersion   lens   and 
mechanical  stage  ;  cedar-wood  oil. 

The  following  procedure  is  then  to  be  adopted  : 
1.  Collection  of  Blood  for  Serum. — This  is  done  by 
cleansing  the  finger-tip  or  lobe  of  the  ear  with  warm 
soap  and  water  or  2  per  cent,  lysol  solution,  drying,  and 
rubbing  well  with  a  small  piece  of  lint  saturated  with 
ether.  When  the  latter  has  evaporated,  a  prick  is  made 
with  a  needle.  This  is  best  done  decisively,  for  patients 
prefer  one  effective  puncture  to  several  ineffective  ones. 
As  a  rule  they  prefer  the  finger-tip  to  be  utilized,  but 


DETERMINATION  OF  THE  OPSONIC  INDEX     31 

should  the  epidermis  be  obviously  thick  at  the  root  of 
the  nail,  it  is  better  to  employ  the  lobe  of  the  ear.  The 
blood  must  flow  spontaneously,  or  but  very  slight  pressure 
be  employed,  and  the  first  drop  wiped  away,  for,  as  has 
been  shown,  the  opsonic  content  of  the  plasma  of  muscle 
and  the  subcutaneous  tissues  is  considerably  higher  than 
that  of  the  blood.  On  approximating  one  of  the  capillary 
ends  of  the  tube  to  the  blood,  the  latter  will  flow  spon- 
taneously into  it.  Three  or  four  drops  of  blood  will 
suffice.  The  tube  must  now  be  sealed  off,  and  here  a 
word  of  caution  is  necessary.  Opsonins  are  readily 
destroyed  by  heating  to  60°  C.  ;  the  blood  must,  therefore, 
not  be  heated.  All  risk  of  this  is  avoided  by  gently 
warming  the  end  of  the  tube  away  from  the  blood,  and 
then  sealing  off  this  end.  Lay  the  tube  down  flat,  and 
allow  it  to  cool.  In  doing  so  the  blood  is  sucked  back 
from  the  unsealed  capillary  end  by  the  vacuum  produced 
by  the  contraction  of  the  contained  air  as  it  cools.  When 
this  has  occurred,  that  end  also  may  be  sealed  off  in  the 
tip  of  the  flame.  These  precautions  are  far  from  un- 
necessary, for  I  have  seen  many  samples  of  blood  quite 
spoilt  in  the  collecting. 

2.  Preparation  of  the  Blood-Cells. — It  matters  not  whence 
the  blood  for  this  purpose  is  collected  provided  not  from 
a  sufferer  from  disease  of  the  lymphatic  system  ;  or  from 
an  individual  whose  red  blood  -  cells  are  capable  of 
agglutination  either  by  their  own  serum  or  by  that  from 
any  other  source.  As  Fleming1  has  pointed  out,  this  is 
particularly  liable  to  occur  in  the  case  of  infected  indi- 
viduals, and  the  effect  of  agglutination  of  the  red  cells  in 
an  opsonic  mixture  is  to  give  an  unduly  high  phagocytic 
count. 

1  Practitioner,  May,  1908,  p.  607. 


32  VACCINE  THERAPY 

The  blood  should  be  collected  aseptically  to  prevent 
contamination  with  organisms  which  will  grow  rapidly 
in  such  a  favourable  medium,  and  prove  troublesome, 
perhaps,  when  the  time  comes  for  counting  the  slides. 
The  collection  is  done  in  one  of  the  T\-inch  glass  pipettes, 
to  which  a  strong  rubber  teat  has  been  fixed.  A  little  of 
the  sodium  citrate  solution  is  first  sucked  up  to  prevent 
coagulation,  then  the  blood,  which  is  at  once  transferred 
to  a  tube  containing  more  of  the  sodium  citrate  solution. 
Blood  may  be  added  to  the  citrate  in  the  proportion  of 
1  to  5. 

The  citrate,  by  precipitating  the  calcium  salts  of  the 
blood,  effectually  prevents  coagulation.  The  citrated 
blood  is  now  transferred  to  the  centrifuge  tubes  and 
thoroughly  centrif ugalized .  A  very  considerable  speed 
— 10,000  revolutions  per  minute — may  be  advantageously 
employed  ;  the  corpuscles  will  be  thrown  down  quickly, 
and  yet  escape  damage.  It  is  to  be  remembered  that 
the  white  cells  are  lighter  than  the  red,  and  will  therefore 
be  thrown  down  last.  It  is  well  to  continue  the  opera- 
tion till  a  distinct  white  layer  is  seen  lying  upon  the 
layer  of  reds,  for  efficient  centrifugalization  means  nume- 
rous white  cells,  and  so  greater  facilities  in  counting.  The 
clear  supernatant  citrate  solution  is  pipetted  off,  care 
being  taken  not  to  disturb  the  white  layer.  Some  of  the 
0-8  per  cent,  sodium  chloride  solution  is  now  added  to 
the  cells,  and  these  thoroughly  mixed  up  with  it  and 
again  thrown  down.  Concentration  of  the  white  cells 
may  be  effected  by  removing  the  upper  layer  of  cells 
from  one  tube,  adding  these  to  the  second  tube,  the  lower 
layer  in  the  first  being  then  thrown  away.  The  washing 
with  normal  saline  solution  is  repeated  once  or  twice.  As 
much  of  the  liquid  as  possible  is  finally  removed  ;  the 


DETERMINATION  OF  THE  OPSONIC  INDEX     33 

cells,  thoroughly  mingled  with  what  is  left,  are  then  ready 
for  use.  A  little  plug  of  cotton-wool  will  prevent  access 
of  organisms  from  the  air. 

3.  Preparation  of  the  Bacterial  Emulsion. — This,  with 
one  exception — that  of  the  tubercle  bacillus — has  always 
to  be  prepared  fresh.  Young  organisms  stain  better  and 
more  uniformly  than  old.  It  is,  therefore,  better  to 
employ  as  recent  a  culture  as  possible,  especially  in  the 
case  of  such  organisms  as  that  of  Morax-Axenfeld,  which 
begin  to  involute  even  before  eighteen  hours.  A  twelve- 
to  sixteen-hour-old  culture  on  an  appropriate  medium — 
such  as  agar  for  staphylococci,  streptococci,  coli,  etc.  ; 
blood-agar  for  gonococci  ;  nutrose  ascitic  agar  for  Bacillus 
Morax-Axenfeld  or  Micrococcus  catarrhalis — is,  therefore, 
to  be  employed.  If  the  growth  be  a  very  copious  one  it  is 
best  to  take  a  loopful  of  the  culture  on  a  platinum  wire, 
and  carefully  emulsify  it  in  a  watch-glass  with  a  little  of 
the  O'l  per  cent.  NaCl  solution.  If  the  growth  be  scanty, 
then  it  is  best  to  pour  a  few  drops  of  the  solution  into 
the  culture-tube  and  emulsify  it  in  situ.  The  turbid 
emulsion  thus  produced  contains  many  clumps,  which 
are  to  be  thrown  down  by  means  of  the  centrifuge.  A 
minute  or  two  will  usually  suffice  at  a  high  speed,  but 
experience  alone  will  teach  just  how  long  it  should  be 
continued.  In  any  case,  it  must  be  efficient,  for  nothing 
is  more  annoying  than  to  find  clumps  in  the  films  when 
everything  has  been  completed,  for  if  accuracy  be  desired 
the  whole  process  must  then  be  repeated.  Experience, 
again,  alone  will  teach  whether  the  emulsion  requires 
further  dilution.  The  opacity  of  an  emulsion,  say,  of 
gonococcus  must  be  much  greater  than  that  of  emulsions 
of  staphylococci  or  Friedlander's  bacillus  in  order  to  give 
the  same  count  in  the  normals.  A  strength  which  will 

3 


34  VACCINE  THERAPY 

give  a  count  of  about  250  to  350  bacteria  in  the  100  cells 
of  the  normal  should  be  aimed  at.  In  the  instance  of  the 
tubercle  bacillus  an  emulsion  once  made  and  found  satis- 
factory may  be  preserved  sealed  up  in  capillary  tubes  for 
practically  any  length  of  time,  especially  if  the  bacteria 
have  been  killed  by  heating  to  70°  C.  for  one  hour.  When 
wanted,  all  that  is  necessary  is  thoroughly  to  shake  up 
the  emulsion  and  give  it  a  few  sharp  turns  in  the  centrifuge 
to  throw  down  any  clumps  which  may  be  present. 

These  preliminaries  over,  we  now  take  as  many  of  the 
fine  long-drawn  capillary  pipettes  as  there  are  sera  to  be 
investigated.  They  should  be  chosen  of  as  equal  bore  as 
possible.  It  is  advisable  for  them  to  have  been  sealed 
off  at  the  fine  extremity,  plugged  with  cotton-wool  at  the 
other,  and  dry  sterilized.  The  fine  ends  are  cut  off 
square  by  means  of  a  file  scratch,  and  marks  made  with 
a  grease-pencil  about  1  centimetre  from  the  ends.  The 
content  as  far  as  this  mark  is  the  unit  volume  in  each 
case.  To  the  plugged  ends  are  fitted  the  strong  rubber 
teats,  and  each  pipette  is  marked  with  a  number  corre- 
sponding to  a  serum.  The  rubber  teat  is  now  held  between 
thumb  and  forefinger  and  gently  compressed,  the  capillary 
end  inserted  into  the  well-mixed  blood-cells,  and  the  unit 
volume  drawn  up  by  slightly  relaxing  the  pressure  on  the 
teat.  Next  a  tiny  bubble  of  air  is  allowed  to  enter,  a 
second  and  third  volume  of  blood-cells  being  drawn  up  in 
similar  fashion,  each  separated  from  the  next  by  a  bubble 
of  air.  A  volume  of  the  bacillary  emulsion  is  now  drawn 
in  with  especial  accuracy,  then  a  bubble  of  air  ;  finally, 
2  volumes  of  the  serum,  which  must  be  taken  up  free 
from  admixture  with  red  cells,  as  these  tend  to  produce 
an  unduly  low  phagocytosis.  We  thus  have  in  order  in 
the  pipette  3  volumes  of  blood-cells,  1  volume  of  emulsion, 


DETERMINATION  OF  THE  OPSONIC  INDEX     35 

2  volumes  of  serum,  each  volume  being  separated  from 
the  adjoining  by  means  of  a  bubble  of  air.  This  is 
the  procedure  usually  followed,  but  if  the  emulsion  be 
suspected  to  be  too  thin,  then  2  volumes  of  blood-cells, 
1  volume  of  emulsion,  and  1  of  serum  may  be  employed, 
or  the  original  1,  1,  1  of  Wright.  The  order — cells, 
emulsion,  serum — should,  however,  always  be  followed, 
for  in  this  way  contamination  of  the  cells  by  the  bacterial 
emulsion,  or  introduction  of  opsonin  from  the  serum  into 
the  emulsion,  is  avoided.  By  gentle  pressure  on  the  teat 
the  several  volumes  are  expressed  on  to  a  clean  glass 
slide,  and  thoroughly  mixed  by  alternately  sucking  the 
mixture  into  the  pipette  and  squeezing  it  out  again  upon 
the  glass  slide.  Only  by  thorough  mixing  can  a  satis- 
factory count  be  ultimately  obtained.  The  mixture  is 
finally  withdrawn  as  completely  as  possible  some  little 
distance  into  the  pipette,  and  the  extremity  sealed  off 
in  the  flame. 

This  operation  is  repeated  with  each  serum.  The  several 
pipettes,  carefully  labelled,  are  then  placed  in  the  incu- 
bator at  37°  C.  for  fifteen  minutes.  By  means  of  a  file- 
scratch  the  ends  are  then  cut  off,  the  content  of  each 
blown  out  on  to  a  clean  glass  slide,  and  very  carefully 
mixed.  Half  the  drop  is  then  transferred  to  a  second 
slide,  and  two  blood-films  prepared  by  the  slide  method — 
i.e.,  by  drawing  the  extremity  of  one  slide  held  at  an 
acute  angle  over  the  surface  of  the  other  upon  which  the 
drop  of  blood  has  been  placed. 

Mention  may  here  be  made  of  two  points  of  some 
importance  :  Firstly,  the  thickness  of  the  blood-film 
depends  partly  upon  the  pressure  employed  in  the 
spreading,  and  to  a  greater  extent  upon  the  inclination 
of  the  moving  slide  to  the  stationary  one.  The  more 

3—2 


36  VACCINE  THERAPY 

vertical  the  former  is  held  the  thinner  the  film,  and,  con- 
versely, the  more  acute  the  angle  the  thicker  the  film. 
Now,  the  ideal  film  is  one  in  which  the  corpuscles  do  not 
lie  one  upon  the  other,  but  are  even  separated  by  distinct 
intervals,  for  in  such  an  one  the  white  blood-cells  flatten 
out,  and  consequently  are  of  larger  size.  The  contained 
bacteria  are,  therefore,  much  more  easily  distinguished 
after  staining,  and  counting  is  consequently  facilitated. 
Films  containing  tubercle  bacilli  may,  however,  be  spread 
rather  thicker  than  in  the  case  of  other  organisms,  for 
the  staining  methods  are  more  drastic,  the  organisms 
show  up  more  clearly,  and  the  red  cells  are  practically 
invisible. 

To  obtain  the  best  films  firm  pressure  should,  therefore, 
be  employed,  and  the  slides  should  be  held  at  an  angle 
of  60  degrees  to  one  another. 

Secondly,  owing  to  their  greater  viscosity,  the  white 
cells  tend  not  only  to  be  drawn  towards  the  end  of  the 
film,  but  also  to  run  to  the  edges.  These  facts  may  be 
turned  to  practical  advantage  if  the  precaution  be  taken 
not  to  place  too  large  a  quantity  of  blood  upon  the  slide. 
Instead  of  using  a  slide  of  ordinary  breadth  for  spreading, 
one  may  be  bisected  longitudinally  by  means  of  a  glazier's 
diamond,  and  this  half-slide  employed.  If  the  drop  of 
blood  be  then  placed  at  the  mid-point  of  the  breadth  of  the 
slide,  but  near  one  extremity,  and  the  half-slide  used  as  a 
spreader,  a  film  is  obtained  with  two  edges  lying  some 
little  distance  from  the  margins  of  the  slide,  and  along 
these  edges  the  white  cells  will  be  found  collected.  Next, 
by  moving  the  spreader  in  a  series  of  little  jerks  instead 
of  with  a  uniform  motion,  a  number  of  little  valleys,  as 
it  were,  are  made  in  the  film,  in  which  the  white  cells 
collect  just  as  they  do  along  the  edges. 


DETERMINATION  OF  THE  OPSONIC  INDEX     37 

Attention  given  to  these  trifling  details  is  well  repaid 
by  the  additional  ease  with  which  the  slides  are  counted. 

The  films,  having  been  spread,  are  then  allowed  to  dry 
in  the  air.  One  of  each  is  reserved  in  case  of  accident  ; 
the  others  are  treated  as  follows  :  If  containing  tubercle 
bacilli,  they  are  then  fixed  for  fifteen  minutes  in  methylic 
alcohol,  or  for  one  hour  in  a  mixture  of  equal  volumes 
of  ethyl  alcohol  and  ether,  stained  by  the  Ziehl-Nielsen 
method,  and  counterstained  with  toluedene  blue.  Five 
minutes'  application  of  the  latter  stain,  followed  by 
thorough  washing  under  the  tap,  will  show  up  the  bodies 
of  the  white  cells  most  effectually.  For  any  other 
organism  than  the  tubercle  bacillus  the  films  are  best 
stained  according  to  Leishman's  method. 

Next,  with  TV-inch  oil-immersion  lens  and  a  mechanical 
stage  the  numbers  of  bacteria  contained  in  each  consecu- 
tive five  polymorphonuclear  leucocytes  are  noted  till  100 
cells  have  been  counted.  No  estimation  can  be  con- 
sidered satisfactory  unless  the  numbers  of  bacteria  found 
in  each  five  cells  approximate  to  each  other.  The  follow- 
ing points  may  here  be  noted,  and  too  much  stress  cannot 
possibly  be  laid  upon  their  importance  if  accuracy  be 
desired  in  the  estimation  :  Firstly,  the  advisability  of 
counting  as  many  cells  and  their  bacterial  contents  as 
possible.  Reliance  is  commonly  placed  upon  a  count  of 
fifty  cells.  I  would  maintain  that  no  amount  of  care  at 
every  stage  will  insure  an  accurate  result  with  such  a 
count  ;  100  cells  is  the  minimum  number  that  should  be 
observed.  Secondly,  the  occurrence  of  bacterial  clumps 
of  any  size  in  a  film,  especially  if  these  lie  upon  any  of 
the  cells,  should  damn  such  a  film  beyond  redemption. 
There  is  nothing  for  it  but  to  repeat  that  experiment 
with  that  serum,  and,  of  course,  with  a  fresh  normal. 


38  VACCINE  THERAPY 

Thirdly,  the  occurrence  of  clumps  of  leucocytes,  especially 
if  these  be  held  together  by  threads  of  fibrin,  should 
render  the  experiment  null  and  void.  Once  more  repeti- 
tion is  more  than  advisable.  Of  course,  both  these  last 
difficulties  should  not  occur.  They  are,  as  a  rule,  the 
result  simply  of  lack  of  care  in  preparing  the  blood-cells 
and  the  bacterial  emulsion. 

The  determination  of  the  index  is  now  completed  as 
follows  :  The  normal  serum  is  taken  as  having  an  opsonic 
index  of  unity.  The  number  of  bacteria  found  in  100 
cells  of  each  of  the  patient's  slides  divided  by  the  number 
in  100  cells  of  the  normal  slide  gives  their  respective 
indices.  To  recapitulate,  then,  the  points  of  importance, 
by  observance  of  which  accuracy  can  alone  be  secured 
and  much  time  and  trouble  saved  : 

1.  The  solutions  used  for  the  preparation  of  the  blood- 
cells  must  be  quite  free  from  hairs  and  filaments,  for  these 
inevitably  entangle  the  white  cells  and  lead  to  clumps 
in  the  films. 

2.  The  blood  must  be  received  into  sufficient  citrate 
solution  to  insure  complete  prevention  of  clotting,  and 
the  cells,  when  washing  is  complete,  must  be  thoroughly 
mixed  to  insure  equal  numbers   of  leucocytes  in  equal 
volumes. 

3.  The  bacterial  emulsions  must  be  thoroughly  centri- 
fugalized  to  free  them  from  all  clumps,  and  growths  of 
not  more  than  eighteen  hours  should  be  employed  for 
their  preparation.     The   strength   should   be   such   that 
250    to    350    bacteria    are    found    in    100   cells  of   the 
normal. 

4.  The  several  volumes  must  be  thoroughly  mixed,  both 
before  and  after  incubation,  to  secure  uniformity  of  count 
in  each  series  of  five  cells. 


DETERMINATION  OF  THE  OPSONIC  INDEX     39 

5.  The  films  must  be  spread  thinly  to  insure  the  poly- 
morphs  being  as  large  as  possible. 

6.  Staining    must    be    satisfactory,   and  the   cell-body 
shown  up.     If  this  prove  not  so,  the  reserve  slide  must 
be  stained. 

7.  At  least  100  cells  in  each  film  should  be  counted. 

8.  If  at  the  first  attempt  an  unsatisfactory  result  is 
obtained,  whether  from  clumps  of  cells  or  bacteria,  or 
from  too  few  white  cells  being  present  in  the  films,  per- 
severance in  counting  imperfect  films  is  to  be  deprecated. 
Time  and  temper  will  alike  be  saved  by  repeating  the 
whole  estimation. 

Brief  reference  may  here  be  made  to  recent  attempts 
at  shortening  the  technique  in  determinations  of  tuber- 
culo-opsonic  indices  by  the  employment  of  emulsions  of 
killed  organisms  which  have  been  already  stained  with 
carbol  fuchsin.  Although  one  or  two  observers1  have 
reported  favourable  results,  the  more  general  experience 
is  that  accuracy  cannot  be  thereby  secured.  The  chief 
difficulty  appears  to  be  in  the  preparation  of  a  satis- 
factory emulsion  free  from  clumps.  Staining,  whether 
by  weak  and  cold  or  hot  and  strong  fuchsin  solutions, 
seems  to  affect  the  organisms  in  such  a  way  that  centri- 
fugalization,  Avhich  throws  down  the  clumps,  also  suffices 
to  throw  down  the  single  bacilli. 

THE  QUESTION  OF  THE  ACCURACY  OF  THIS  METHOD  OF 
ESTIMATING  THE  OPSONIC  CONTENT  OF  THE  BLOOD. 

It  must  be  admitted  that  the  reliability  of  estimations 
of  the  opsonic  content  of  the  blood,  conducted  according 
to  the  above  technique,  or  slight  modifications  of  it,  has 

1  Campbell,  British  Medical  Journal,  April  13,  1907,  p.  866. 


40  VACCINE  THERAPY 

been  rudely  assailed  during  the  past  two  years— among 
others  by  Simon.  Lamar.  and  Bispham.1  and  by  Walker2 
in  America,  and  by  FitzGerald,  Whiteman.  and  Strange- 
ways3  in  England. 

In  these  un-Socratic  days  the  honesty  of  all.  both  of 
those  upholding  and  of  those  opposing  any  given  pro- 
cedure, is  to  be  assumed.  Against  their  experiments  and 
results,  then,  are  to  be  placed  those  of  Wright  and  his 
co-workers,  Bullock,  White,4  the  author,  and  many 
others.  Upon  the  one  hand  are  those  who  obtain  un- 
reliable results ;  upon  the  other  those  who  truly  believe. 
and.  as  far  as  figures  can  substantiate  a  belief,  find  sup- 
port in  their  figures  for  the  belief,  that  in  their  hands  the 
method  affords  reliable  results. 

It  thus  follows  that  there  are  two  classes  of  observers  : 
(1)  those  who  can  estimate  an  index  accurately  by  these 
methods  ;  and  (2)  those  who  cannot  estimate  an  index 
accurately  by  these  methods — just  as  there  are  surgeons 
who  can  perform  perfectly  the  delicate  operations  advo- 
cated by  Mayo  Robson  and  by  Arbuthnot  Lane,  and  others 
who  cannot.  Upon  the  one  hand,  the  possibility  of  the 
proper  performance  of  these  operations  cannot  be  im- 
pugned by  any  multiplicity  of  ill-results  in  unskilled 
hands  ;  upon  the  other  hand,  the  possibility  of  the  accu- 
rate estimation  by  this  method  of  the  opsonic  content  of 
the  blood  is  not  disproved  in  the  slightest  by  any  number 
of  inaccurate  estimations  in  unskilled  hands. 

Let  me  not  be  misunderstood.     I  make  no  claim  that 

1  Journal  of  Experimental  Medicine,  August,  1906,  p.  651 ;  Hid.. 
September,  1907,  p.  485. 

2  Journal  of  Medical  Research,  July,  1907,  p.  521. 

3  Bulletin  of  Committee  for  Study  of  Special  Diseases,  Cambridge, 
vol.  i..  No.  8. 

4  Practitioner,  May,  1908,  p.  639. 


DETERMINATION  OF  THE  OPSONIC  INDEX     41 

the  accuracy  of  the  method  is  comparable  with  that,  say, 
of  the  determinations  of  the  various  physical  coefficients. 
There  are  pitfalls  innumerable  for  the  unwary,  and  even 
the  most  skilled  experimenter  will  every  now  and  again 
obtain  a  wrong  result  ;  but  here  is  an  important  point  : 
he  will  know  that  he  is  obtaining  an  unreliable  result,  and 
will  either  repeat  the  whole  estimation  or  count  a  much 
larger  number  of  cells  than  usual,  and  so  minimize  the 
error.  Fleming  (v.s.)1  appositely  remarks  :  '  In  this  con- 
nection it  should  be  pointed  out  that  it  is  a  great  mistake 
to  have  any  arbitrary  number  of  leucocytes  which  one 
counts,  neither  counting  more  nor  less,  whatever  the  con- 
ditions may  be  ' — a  remark  with  which  I  most  completely 
agree  ;  and  again  :  '  Intelligence  must  be  brought  to  bear 
on  the  subject  in  hand.' 

Despite  this,  it  cannot  but  be  admitted  that  even  in 
the  hands  of  the  most  skilled  there  is,  as  Greenwood2 
points  out,  an  error  inherent  in  any  such  method  which 
is  quite  inevitable — an  error,  however,  which  only  rarely 
exceeds  10  per  cent.,  and  is  usually  about  5  to  6  per 
cent.,  and  is  of  little  or  no  practical  importance. 


OTHER  METHODS  OF  ESTIMATING  THE  OPSONIC  CONTENT 
OF  THE  BLOOD. 

Inasmuch,  then,  as  the  above  method  of  determining 
the  opsonic  index  must  be  admitted  to  be  a  very  delicate 
and  somewhat  laborious  and  difficult  matter,  and  one, 
moreover,  which  is  unsuited  to  a  certain  proportion  of 
workers,  any  other  method  which  is  less  laborious,  less 
difficult,  and  suitable  for  all,  can  only  be  regarded  as  in  the 
highest  degree  desirable. 

1  Practitioner,  May,  1908,  p.  627.  2  Ibid.,  p.  641. 


42  VACCINE  THERAPY 

Several  attempts  have  been  made  in  this  direction. 
Thus,  Simon  (v.s.)  would  substitute  an  index  obtained  by 
diluting  the  blood  in  varying  proportion  (ten  to  thirty 
times),  and  after  incubating  with  a  bacterial  emulsion 
of  considerable  strength,  comparing  the  percentage  of 
phagocyting  leucocytes  in  the  specimen  of  blood  under 
investigation  with  the  figure  obtained  after  a  similar 
procedure  with  a  specimen  of  normal  blood.  This  he 
calls  the  'percentage  index,'  and  finds  it  sometimes  to 
agree  well  with  the  opsonic  index,  sometimes  to  differ 
considerably  from  it,  in  which  event  he  prefers  to  follow 
the  guidance  of  his  percentage  index.  As  to  the  accuracy 
of  the  method  I  can  offer  no  opinion,  but  it  is  admittedly 
even  longer  than  the  method  it  seeks  to  displace,  and  to 
my  mind  has  this  very  grave  objection  :  the  dilution  of 
the  serum.  It  is  perfectly  true  that  if  the  opsonizing 
power  of  the  serum  of  an  injected  individual  be  com- 
pared with  that  of  the  serum  of  a  healthy  individual, 
marked  differences  are  revealed  according  as  the  undi- 
luted sera  or  the  sera  in  various  degrees  of  dilution  are 
compared.  As  dilution  proceeds,  it  will  sometimes  be  found 
that  the  opsonizing  power  of  the  immune  serum  rapidly 
falls  off  in  comparison  with  that  of  the  normal  serum. 
Thus,  an  index  of  1-4  may  be  obtained  for  the  undiluted 
immune  serum,  and  an  index  of  only  0-8  for  the  same 
serum  in  a  dilution  of  1  in  20.  Certain  observers — as 
Simon  and  Walker  (v.s.),  who  estimate  the  opsonic 
index  by  means  of  diluted  sera — consider  examination 
of  such  to  afford  the  better  idea  of  the  immunizing 
power  of  the  blood.  I  would  maintain  that  they  are 
conducting  an  investigation — the  results  of  which  are 
doubtless  of  value — under  conditions  which  do  not  in 
the  least  obtain  in  any  pathological  condition  in  the 


DETERMINATION  OF  THE  OPSONIC  INDEX     43 

human  organism.  If  possible,  what  one  desires  to  ascer- 
tain is  the  opsonizing  power,  not  even  of  the  blood-serum, 
but  of  the  blood-plasma,  in  the  condition  in  which  it 
actually  is  in  the  human  organism.  Moreover,  not  even 
in  a  suppurating  focus  nor  in  an  exudate  of  pus  do  the 
bacteria  ever  present  any  such  ratio  to  the  phagocytes 
as  they  employ  in  their  phagocyting  mixtures.  In  order 
to  learn  the  immunizing  response  of  the  body,  say,  in  a 
case  of  streptococca  septica3mial,  where,  perhaps,  ten 
streptococci  can  be  isolated  from  5  c.c.  of  blood,  they 
would  present  an  emulsion  containing  at  least  5,000 
million  organisms  per  c.c.  to  a  mixture  of  blood-cells 
containing,  perhaps,  5,000  to  10,000  phagocytes  per  c.c. 
in  a  serum  diluted  twenty  or  thirty  times.  Can  any  con- 
ditions less  like  these  obtaining  in  the  human  organism 
easily  be  conceived  ? 

The  method  suggested  by  Stewart,1  Dodds,2  and 
Veitch3  has,  on  the  other  hand,  much  to  recommend  it, 
and  most  nearly  of  all  approaches  the  natural  conditions. 
It  is  conducted  as  follows  :  One  volume  of  blood  is  with- 
drawn from  the  patient  in  a  sterilized  capillary  pipette, 
and  at  once  thoroughly  mixed  with  an  equal  volume  of 
1-5  per  cent,  solution  of  sodium  citrate  in  0-8  per  cent 
salt  solution,  and  the  ends  of  the  pipette  sealed.  The 
same  is  done  with  the  control  normal  blood.  These 
mixtures  are  then  preserved  till  required,  and,  according 
to  Stewart,  keep  unaltered  for  twelve  hours,  or,  if  kept  in 
a  refrigerator,  for  three  days. 

The  phagocytic  mixture  is  made  by  taking  two  volumes 
of  the   blood   citrate   mixture   and   one  volume  of  the 

1  Journal  of  Bacteriology,  1908. 

2  British  Medical  Journal,  October  12,  1907,  p.  948. 

3  Journal  of  Pathology  and  Bacteriology,  January,  1908,  p.  353. 


44  VACCINE  THERAPY 

bacillary  emulsion,  and  proceeding  in  the  usual  way. 
The  haemophagocytic  index  thus  determined  is  claimed 
to  agree  well  with  the  opsonic  index,  while  the  method 
affords  a  certain  saving  of  time,  especially  when  only 
two  or  three  bloods  have  to  be  examined,  and  is  perhaps 
more  accurate,  inasmuch  as  clumps  of  leucocytes  very 
rarely  occur.  The  fact  that  the  plasma  is  employed 
instead  of  serum,  and  the  patient's  own  leucocytes,  which 
are  not  altogether  an  indifferent  factor,  are  additional 
recommendations. 


CHAPTER  IV 

PEEPAKATION  OP  THE  VACCINE 

THE  general  consensus  of  opinion  is  that  the  best  possible 
results  are,  as  a  rule,  only  to  be  looked  for  when  organisms 
isolated  from  the  patient's  own  lesion  are  employed  for 
the  manufacture  of  the  vaccine.  Several  considerations 
may,  however,  militate  against  the  advisability  of  this 
procedure.  The  chief  of  these  are  as  follows  : 

1.  Where  the  isolation  of  the  organism  is  so  difficult 
and  tedious  that  the  resultant  loss  of  time  would  fail  to 
compensate  for  the  advantages  obtained.  An  excellent 
example  of  this  is  afforded  in  tubercular  affections. 
Here  we  are  compelled  to  resort  to  inoculation  experi- 
ments, the  animals  usually  selected  for  the  purpose  being 
the  rabbit  or  guinea-pig,  and  the  site  of  inoculation  either 
the  subcutaneous  tissue  of  the  groin  of  the  latter  or  the 
anterior  chamber  of  the  eye  of  the  former.  Of  these  two 
animals,  the  guinea-pig  is  generally  held  to  be  the  more 
susceptible  to  the  tubercle  bacillus,  dying  of  general 
tuberculosis  from  six  to  ten  weeks  after  inoculation, 
according  to  the  virulence  of  the  organism  and  the  number 
introduced.  On  the  other  hand,  if  tuberculous  material 
be  introduced  into  the  anterior  chamber  of  the  eye  of  the 
rabbit,  an  iritis  which  is  almost  pathognomonic  results  in 
from  two  to  four  weeks.  In  either  case  the  loss  of  time 
is  very  considerable.  Nor  is  this  all.  The  growth  of  the 
tubercle  bacillus  is  again  so  slow,  and  the  preparation  of 

45 


46  VACCINE  THERAPY 

tuberculin  so  difficult  an  operation,  that  another  two  or 
three  months  would  be  consumed  in  the  preparation  of 
the  vaccine.  This  is  very  greatly  to  be  regretted,  for 
many  of  the  only  partial  successes  or  even  failures  in 
cases  treated  by  tuberculin  are  possibly  very  largely  due 
to  the  employment  of  stock  tuberculin.  This  question 
will  be  again  referred  to  later. 

A  second  example  of  this  class  of  case  is  afforded  in 
some  chronic  gleets.  The  gonococcus  may  be  visible  in 
smears  of  the  urethral  secretion,  yet,  despite  the  utmost 
care  in  taking  the  cultures,  it  may  prove  impossible  to 
free  the  gonococcus  from  the  contaminating  organisms. 

2.  The  infection,  although  localized,  may  be  of  so  acute 
and  destructive  a  type  that  the  loss  of  even  two  or  three 
days  may  be  of  vital  importance.  An  excellent  example 
of  this  is  seen  in  gonorrhceal  conjunctivitis  in  the  adult. 
Here  prompt  injection  of  a  stock  vaccine  is  obligatory 
immediately  the  patient  is  diagnosed.  I  have  seen  cases 
so  severe  that  total  destruction  of  the  sight  was  inevitable 
in  two  or  three  days,  thereby  completely  held  in  check, 
and,  save  for  the  destruction  which  had  already  occurred, 
cured  within  a  week  (vide  chapter  on  The  Eye). 

.3.  Where  the  infection  is  so  very  chronic  that  it  is 
reasonable  to  suppose  that  the  virulence  of  the  infection 
has  been  greatly  reduced,  though  even  here  it  is  better 
wherever  possible  to  test  the  virulence  by  an  inoculation 
experiment  upon  animals.  Good  examples  of  this  class 
of  case  are  afforded  by — (a)  very  chronic  cases  of  osteo- 
myelitis which  have  been  subjected  to  considerable  surgical 
treatment  ;  (6)  chronic  gonorrhceal  infections,  especially 
old  gleets  in  the  male,  and  tubal  cases  in  the  female. 

4.  A  final  exception  may  be  made  in  the  instance  of 
such  organisms  as  seem  to  be  definite  entities,  and  not  to 


PREPARATION  OF  THE  VACCINE  47 

compose  a  family  group  of  such  closely  related  members 
as  the  streptococci.  So  far  as  we  are  aware,  there  is,  for 
example,  but  one  Bacillus  septus  and  one  Micrococcus 
melitensis ;  yet  even  here  the  better  plan  is  undoubtedly 
the  preparation  of  a  special  vaccine,  unless  other  con- 
siderations are  against  the  adoption  of  this  plan. 

The  method  employed  for  the  isolation  of  the  organisms 
will  vary  according  as  to  whether  we  are  dealing  with  a 
pure  or  a  mixed  infection,  and  this  point  may  be  largely 
determined  by  first  making  smears,  staining  by  Gram's 
method  and  with  methylene  blue,  and  examining  micro- 
scopically. 

Should  the  infection  appear  to  be  unmixed,  then  cultures 
are  to  be  made  at  once  upon  the  medium  best  suited  for 
the  growth  of  the  organism  in  question,  such  as  blood- 
agar  in  the  case  of  pneumococcus,  nutrose  ascitic  agar  or 
blood-agar  in  the  case  of  gonococcus,  agar  in  the  case  of 
staphylococcus,  glycerine  potato  in  case  of  tubercle.  If 
the  infection  be  a  mixed  one,  it  must  be  borne  in  mind 
as  a  most  important  point  that  the  isolation  must  be 
done  as  quickly  and  in  as  few  subcultures  as  possible,  for 
only  thus  is  a  fully  virulent  growth  likely  to  be  obtained. 
Of  any  peculiarities  of  growth  of  an  organism  in  pre- 
sence of  others  advantage  is  therefore  to  be  taken,  and 
cultures  made  from  the  infected  part  with  every  possible 
care. 

A  few  details  which  have  been  found  useful  may  here 
be  given. 

TUBERCLE  BACILLUS. 

The  tubercle  bacillus  is  mentioned  because  the  author 
feels  convinced  that  more  and  more  will  it  be  found 
advantageous  in  difficult  cases  to  continue  injections 


48  VACCINE  THERAPY 

with  a  stock  tuberculin  only  while  a  special  one  is  in  pro- 
cess of  manufacture. 

The  peculiarity  of  localized  tubercular  affections  is  the 
paucity  in  the  number  of  bacilli  present.  This  holds  true 
whether  it  is  the  pus  from  the  tubercular  joint  or  the 
tissues  of  a  tubercular  gland  or  conjunctiva.  In  the  case 
of  tubercular  bladders  and  kidneys,  however,  very  large 
numbers  of  bacilli  may  be  discharged  in  the  urine.  Some 
means  must  therefore  be  adopted  not  only  of  freeing 
the  tubercle  bacilli  from  contaminations,  but  also  for 
increasing  their  numbers.  This  is  done,  as  said  before, 
by  inoculating  a  rabbit  or  guinea-pig.  If  the  material 
be  pus  or  solid  gland,  this  is  done  directly  ;  if  conjunctiva, 
care  must  be  taken  to  cleanse  the  eye  thoroughly  with 
sterile  saline  before  removing  the  piece  of  conjunctiva ; 
if  pus  in  urine  the  bacilli  are  to  be  separated  by  thoroughly 
centrifuging  the  urine  which  has  been  drawn  off  with  a 
catheter,  washed  well  with  sterilized  water,  and  again 
centrifuged,  repeating  this  several  times.  The  final 
deposit  may  then  be  employed  like  any  other  inoculum. 
Immediately  the  animal  has  died,  or  as  soon  as  caseous 
glands  are  to  be  felt,  or  after  three  to  four  weeks  in  the 
case  of  injection  into  the  anterior  chamber  of  the  eye  of 
the  rabbit,  death  is  produced  by  means  of  chloroform  ; 
the  animal  is  opened  with  all  antiseptic  and  aseptic  pre- 
cautions, and  culture-tubes  of  glycerinized  potato  in- 
seminated with  as  large  portions  of  the  diseased  glands 
or  iris  as  is  possible.  The  tubes  are  then  sealed  up  and 
incubated  at  37°  C.  for  six  to  eight  weeks,  when  a  copious 
growth  of  tubercle  bacilli  should  be  available  for  the 
manufacture  of  tuberculin.  Unfortunately,  there  are 
cases  where  the  tubercle  bacilli  thus  obtained,  often  in 
considerable  numbers,  from  the  glands  and  spleen  of 


PREPARATION  OF  THE  VACCINE  49 

the  injected  animal  refuse  to  grow  in  artificial  cultures. 
The  following  modification  of  an  old  method  has  been 
given  me  by  Williamson  as  very  useful  in  obtaining 
cultures  direct  from  sputum  :  A  suitable  lump  is  chosen, 
washed  thoroughly  in  sterile  salt  solution,  and  incu- 
bated at  37°  C.  for  ten  to  fourteen  days  with  pure  glycerine 
in  the  portion  of  1  part  of  sputum  to  4  parts  of  glycerine. 
The  mixture  is  then  employed  for  the  insemination  of 
broth,  potato,  or  agar. 

STAPHYLOCOCCUS  ALBUS  AND  AURETJS. 

(a)  In    cases    of    acne,    furunculosis    and   sycosis    are 
generally  present  in  a  state  of  purity,  but  often  in  limited 
numbers.     It  is  not,  therefore,  advisable  to  do  more  than 
wash  the  surface  of  the  skin  with  warm  soap  and  water. 
The  pus  should  then  be  carefully  expressed  from  a  solid 
pustule,  if  possible,  for  the  softer  ones  may  prove  sterile, 
and  a  series  of  two  or  three  sloped  agar-tubes  inseminated 
with  varying  amounts   of  the  pus,   and  incubated  for 
twenty-four  hours  at  37°  C.     A  colony  may  then  usually 
be  picked  out  and  employed  to  plant  the  required  cultures. 

(b)  In  cases  of  periostitis  and  osteomyelitis  the  infec- 
tion may  be  a  mixed  one,  when  it  is  perhaps  advisable 
to  mix  up  some  of  the  pus  with  a  tube  of  broth  and  use 
some  of  this,  either  directly  or  after  twenty-four  hours' 
incubation,  to  make  a  series  of  agar-plates,  from  which  a 
colony  may  then  be  selected. 

STREPTOCOCCUS. 

The  range  of  utility  of  streptococcal  vaccines  will  be 
considered  later  ;  suffice  to  say  here  that  cultures  may 
have  to  be  obtained  from  pus,  fibrinous  exudate,  or  the 

4 


50  VACCINE  THERAPY 

blood.  Should  microscopic  examination  of  films  reveal  no 
organisms  other  than  streptococci,  cultures  may  be  made 
at  once  upon  agar ;  otherwise  agar-plates  must  be  made 
from  some  of  the  material  after  mixing  it  up  with  broth. 
I  have  found  it  highly  advantageous  in  these  cases  to 
incubate  the  broth  mixture  for  twenty-four  hours  at 
37°  C.  before  preparing  plates.  On  agar  streptococci 
grow  much  more  slowly  than  other  organisms,  especially 
staphylococci,  whereas  in  broth  this  is  not  only  not  the 
case,  but  the  streptococcal  colonies  also  tend  to  fall  to  the 
bottom  of  the  broth.  Slight  centrifugalization  accentu- 
ates this  tendency.  The  supernatant  liquid  may  then  be 
poured  off,  and  agar-plates  prepared  from  the  concen- 
trated streptococcal  emulsion.  A  colony  having  thus  been 
isolated,  subcultures  are  to  be  made  upon  sloped  agar- 
tubes.  The  growth  after  eighteen  to  twenty-four  hours 
is  so  slight  that  several  tubes  must  be  employed.  A 
better  way  is  to  employ  agar-plates  inseminated  by  means 
of  a  glass  rod,  as  the  surface  for  growth  is  thus  greatly 
increased. 

If  cultures  are  to  be  made  from  the  blood,  it  is  necessary 
to  withdraw  quite  a  considerable  quantity — about  5  c.c. 
— from  one  of  the  large  veins  in  the  antecubital  fossa. 
The  skin  is  thoroughly  washed  with  warm  soap  and  water, 
and  then  with  sterilized  water.  A  bandage  is  applied 
tightly  well  above  the  elbow.  Into  a  10-c.c.  syringe  which 
has  been  well  boiled  about  1  c.c.  of  sterilized  2  per  cent, 
sodium  citrate  solution  is  introduced  to  prevent  clotting 
in  the  needle.  The  vein  is  then  punctured  in  a  direction 
against  the  venous  flow,  when  the  blood  will  at  once  flow 
into  the  syringe,  which  can  then  be  filled.  Three  culture- 
tubes,  each  containing  10  c.c.  of  broth,  are  taken.  Into 
the  first  2  c.c.,  into  the  second^!  c.c.,  into  the  third  0-5  c.c. 


PREPARATION  OF  THE  VACCINE  51 

are  then  introduced  ;  they  are  well  shaken  up  and  incu- 
bated at  37°  C.  for  twenty-four  hours.  The  blood  clots 
in  a  few  hours,  the  pigment  sinking  to  the  bottom  of  the 
tube,  leaving  a  translucent  jelly-like  clot  suspended  in 
the  broth.  In  this  clot  the  colonies  develop  as  isolated 
masses,  which  may  be  easily  removed  by  means  of  a 
pipette  and  used  to  inseminate  agar  tubes  or  plates. 


GONOCOCCUS. 

This  very  delicate  organism  may  require  particular  care 
in  isolation.  In  cases  of  gonorrhceal  conjunctivitis  it  is, 
however,  present  in  a  state  of  practical  purity.  It  is  only 
necessary  to  wash  the  eye  out  with  sterilized  water. 
After  waiting  a  few  minutes,  the  eye  being  kept  closed 
in  the  meanwhile,  small  quantities  of  the  exudate  may 
be  taken  up  with  a  sterilized  platinum  loop  and  used  to 
inoculate  sloped  tubes  of  blood-agar  ;  or,  better  still, 
plates  of  blood-agar  may  be  inseminated  by  means  of 
successive  strokes  of  one  or  two  loopfuls  of  the  exudate. 
In  this  way  distinct  colonies  are  usually  to  be  seen  after 
twenty-four  to  thirty-six  hours'  incubation  at  37°  C.  In 
urethral  cases  it  is  always  well  to  take  particular  pains  in 
cleansing  the  external  meatus.  The  penis  is  held  just 
behind  the  glans,  the  external  meatus  being  held  closed. 
The  whole  of  the  glans  is  then  well  cleansed  with  warm 
soap  and  water,  then  with  weak  antiseptic,  finally  with 
sterilized  water.  Any  pus  in  the  extremity  of  the  urethra 
is  then  squeezed  out  and  wiped  off  with  damp  sterile  wool. 
The  pus  from  farther  back  is  then  expressed,  received 
upon  the  platinum  loop,  and  used  to  plant  cultures  as 
before.  In  chronic  cases  it  may  be  necessary  to  pass  the 
loop  a  little  way  into  the  urethra.  It  is  in  these  cases 

4—2 


52  VACCINE  THERAPY 

well  to  remember  that  the  larger  number  of  cocci  are  to 
be  found  in  the  thin  serous  discharge  rather  than  in  the 
grumous.  Sometimes,  despite  all  care,  numerous  attempts 
will  fail  to  isolate  the  gonococcus  in  very  chronic  cases. 
It  only  remains  then  to  employ  a  stock  vaccine. 

A  colony  of  pure  gonococci  having  been  isolated,  fresh 
cultures  are  now  to  be  planted.  For  this  purpose  we 
have  the  choice  of  two  media.  Freshly  prepared  blood- 
agar  made  with  human  blood,  which  is  thoroughly  maxed 
up  with  the  agar  and  tints  it  a  bright  red.  The  medium 
should  be  quite  moist,  and  is  much  superior  to  the  similar 
preparation  made  with  rabbit's  blood.  As  an  alternative 
nutrose  ascitic  agar  is  slightly  inferior,  but  distinctly 
valuable.  It  consists  of  2  per  cent,  agar,  to  which  an 
equal  bulk  of  ascitic  fluid  is  added,  and  2  per  cent,  nutrose. 
It  is  somewhat  difficult  to  prepare,  owing  to  the  insolu- 
bility of  the  nutrose.  Once  made,  however,  it  keeps  very 
well.  Personally,  I  now  always  use  human  blood-agar. 
The  cultures  are  incubated  at  37°  C.  for  eighteen  hours. 


PNEUMOCOCCTJS 

also  grows  best  on  human  blood-agar.  If  successive 
strokes  be  made  either  upon  blood-agar  slopes  or  plates, 
a  pure  culture  can  usually  be  obtained  at  the  first  attempt, 
especially  from  an  empyema  or  otitis  media,  and  in  eye 
cases  if  the  eye  has  been  well  washed  out  previously  with 
sterilized  saline.  In  pneumococcal  endocarditis  cultures 
must  be  made  from  the  blood  in  exactly  the  same  way 
as  described  for  streptococci,  with  the  additional  insemina- 
tion of  a  tube  of  agar,  by  allowing  a  few  drops  of  the 
blood  to  run  over  its  sloped  surface.  From  sputum  its 
recovery  is  more  difficult,  and  is  best  done  by  inserting 


PREPARATION  OF  THE  VACCINE  53 

a  small  piece  of  sputum,  which  has  been  well  washed 
several  times  in  sterile  saline  solution,  under  the  skin  of  a 
rabbit  or  mouse.  In  about  forty-eight  hours  the  animal 
will  die  with  numerous  capsulated  cocci  throughout  its 
blood.  Some  of  the  heart-blood  is  then  taken,  with 
aseptic  precautions,  and  allowed  to  run  over  the  surface 
of  tubes  of  sloped  agar.  In  twenty-four  hours  numerous 
small  transparent  colonies,  like  drops  of  dew,  appear. 
So  rapidly  does  this  organism  lose  its  virulence,  and 
therefore  its  value  for  the  preparation  of  a  vaccine,  that 
even  in  four  or  five  days  after  isolation  from  an  animal's 
body  its  pathogenicity  is  already  diminished.  It  is, 
therefore,  especially  necessary  in  the  case  of  this  organism 
that  a  first  subculture  should  be  employed  for  a  vaccine. 
As  in  the  case  of  the  gonococcus,  the  cultures  should  be 
made  on  human  blood-agar  and  incubated  for  between 
eighteen  and  twenty-four  hours  at  37°  C. 


BACILLUS  COLI  COMMUNIS 

may  be  present  in  a  state  of  purity  in  appendical  and 
extraperitoneal  abscesses,  in  suppuration  round  the  bile- 
ducts,  in  endocarditis,  abscesses  around  the  kidneys,  and 
in  the  Fallopian  tubes.  It  also  occurs  as  a  mixed  infec- 
tion in  inflammation  of  the  urinary  passages,  cystitis,  and 
pyelitis.  Its  isolation  is  a  very  easy  matter  by  means  of 
agar,  or,  better  still,  plates  of  MacConkey's  medium 
(which  consists  of  2  per  cent,  agar,  2  per  cent,  peptone, 
0-5  per  cent,  bile  salts,  and  2  per  cent,  lactose  coloured 
with  neutral  red).  The  bile  salts  inhibit  the  growth  of 
other  organisms  ;  the  Bacillus  coli  communis  ferments  the 
lactose  with  acid  formation,  and  turns  the  neutral  red  a 
canary-yellow  colour  with  greenish  fluorescence,  so  that 


54  VACCINE  THERAPY 

the  colonies  of  this  organism  can  be  readily  picked  out 
and  used  for  the  preparation  of  subcultures  upon  agar 
slopes,  which  should  then  be  incubated  for  eight  to 
twelve  hours. 

BACILLUS  OF  FRIEDLAXDER. 

This  organism  is  especially  easy  of  isolation,  as  it 
appears  to  have  the  power  of  inhibiting  the  growth  of 
almost  all  other  organisms  with  which  it  may  be  admixed. 
For  instance,  if  equal  numbers  of  Staphylococcus  alb'!* 
and  bacillus  of  Friedlander  be  introduced,  each  separately. 
into  a  tube  containing  equal  volumes  of  broth,  and  in- 
cubated at  37°  C.  for  twelve  hours,  equal  numbers  ap- 
proximately of  each  organism  will  be  found  in  equal 
volumes  of  the  cultures  ;  but  if  the  two  organisms  be 
introduced  into  one  tube  of  broth  in  the  ratio  of  1,000 
staphylococci  to  1  bacillus  of  Friedlander.  and  incubated 
at  37°  C.  for  twelve  hours,  the  ratio  found  will  be  hundreds 
of  thousands  of  the  latter  to  one  of  the  former. 

Whatever  the  material  may  be,  pus  or  nasal  mucus, 
all  that  is  necessary,  then,  is  to  mix  up  a  little  of  the 
material  in  a  tube  of  broth,  incubate  for  eight  hours, 
and  then  make  agar-plates  in  the  usual  manner.  Colonies 
of  the  bacillus  of  Friedlander  will  be  found  to  have 
attained  a  considerable  size — |  inch,  say,  in  diameter — 
after  twenty-four  hours'  incubation,  and  from  one  of 
these  agar-tubes  may  be  inseminated. 

THE  BACILLUS  SEPTUS  OR  CORYZ^E  SEGMEXTOSUS. 

This  organism  may  also  readily  be  isolated  from  nasal 
or  pharyngeal  mucus  by  mixing  a  little  of  it  up  in  sterile 
saline  or  broth,  and  from  this  emulsion  preparing:  agar- 


PREPARATION  OF  THE  VACCINE  55 

plates.  Twenty-four  hours'  incubation  at  37°  C.  will  result 
in  the  appearance  of  colonies  of  considerable  size,  from 
which  agar-slopes  may  be  inseminated. 

Differentiation  of  this  organism  from  the  other  members 
of  the  diphtheria  group  is  necessary.  In  microscopical 
appearance  it  differs  somewhat  from  all  the  others.  It 
is  a  short,  rather  thick  bacillus,  with  rounded  ends,  one 
of  which  is  usually  larger  than  the  other.  In  twenty- 
four-hour-old  cultures  it  may  be  so  short  as  to  resemble 
an  oval  coccus.  By  the  third  day  a  very  characteristic 
appearance  is  to  be  seen.  The  protoplasm  of  the  ends 
of  the  bacillus  is  deeply  stained,  leaving  an  unstained 
band  or  septum  across  the  middle,  hence  the  name. 
Involution  forms  are  uncommon  and  not  pronounced, 
while  polar  granules  are  not  revealed  by  Neisser's  method 
of  staining. 

Gordon  considers  that  the  reactions  in  neutral  litmus 
peptone  broth  to  which  1  per  cent,  of  glucose,  lactose, 
saccharose,  and  maltose  have  been  respectively  added, 
serves  to  differentiate  this  organism  completely  from  the 
Bacillus  diphtheria  on  one  hand,  and  from  Xerosis  and 
Hoffmann's  bacillus  on  the  other.  In  the  case  of  the 
Bacillus  septus  there  is  a  tendency  to  acid  formation  in 
all  four  carbohydrate  media,  which  may  not  be  observed 
till  later  than  the  third  day.  The  Bacillus  diphtherias 
produces  a  strongly  acid  reaction  in  glucose  broth  even 
before  three  days,  while  in  the  cases  of  Xerosis  and  Hoff- 
mann's bacillus  an  alkaline  reaction  is  produced  in  all 
four  media. 

The  Bacillus  diphtherioe  is  alone  pathogenic  to  animals. 


56  VACCINE  THERAPY 

THE  MICROCOCCUS  CATARRHALIS 

is  best  isolated  from  nasal  or  pharyngeal  mucus  by 
making  a  succession  of  stroke  cultures  on  blood-serum 
or  blood-agar  plates.  The  organism  is  rather  like  the 
gonococcus  in  microscopical  appearance,  but  differs  from 
it  in  showing  considerable  variation  in  size,  and  also  in 
the  fact  that  the  larger-sized  organisms  tend  to  retain 
the  stain  by  Gram's  method  unless  decolorization  be 
very  thoroughly  carried  out.  In  culture  activities  it 
also  differs  sometimes,  growing  feebly  on  gelatine,  and 
also  in  forming  a  typical  growth  in  broth.  This  consists 
in  the  formation  after  two  or  three  days,  if  undisturbed, 
of  a  gelatinous-looking  sphere  near  the  bottom  of  the 
broth,  covered  with  small  spines,  giving  it  a  sea-urchin 
appearance.  Subcultures  are  best  made  on  blood-agar 
or  on  nutrose  ascitic  agar. 

It  must,  however,  be  noted  that  other  cocci  are  to  be 
found  in  nasal  and  tracheal  mucus  which  closely  resemble 
the  Micrococcus  catarrhalis,  and,  like  it,  fail  to  retain 
the  stain  by  Gram's  method.  Differentiation  of  these 
catarrhalis-like  organisms  from  the  true  Micrococcus 
catarrhalis  is  by  no  means  easy,  but  the  following  points 
are  of  service  : 

1.  The  Micrococcus  catarrhalis  grows  in  pairs  or  tetrads, 
never  in  chains,  like  some  of  the  others. 

2.  It  does  not  produce  acid  in  broth  cultures  containing 
glucose,  saccharose,  maltose,  or  galactose,  whereas  some 
of  the  others  ferment  one  or  more  of  these  sugars. 

3.  The  cocci  of  the  pseudo-catarrhalis  group  are.  as  a 
rule,   smaller   and   more   uniform   in   size   and    staining 
reaction. 


PREPARATION  OF  THE  VACCINE  57 

MORAX-AXENFELD    BACILLUS,    OR   BACILLUS    LiACUNATUS . 

The  isolation  of  this  organism  is  best  carried  out  in 
cases  of  chronic  conjunctivitis  by  taking  up  some  of  the 
thin  serous  secretion  from  near  the  caruncle,  and  making 
successive  strokes  on  tubes  of  blood  -  serum.  After 
twenty-four  or  thirty-six  hours'  incubation  characteristic 
areas  of  liquefaction  of  the  blood-serum  will  be  evident. 

If  films  be  prepared  from  the  bottom  of  one  of  these, 
the  typical  non-Gram  staining  diplobacillus  will  be  seen 
already  beginning  to  involute.  A  pure  colony  having 
been  found,  tubes  of  nutrose  ascitic  agar  are  now  to  be 
inseminated.  Inasmuch  as  this  organism  begins  to  invo- 
lute in  from  eighteen  to  twenty-four  hours  and  growth 
is  but  feeble  (one  tube  yielding  under  favourable  circum- 
stances but  five  or  six  doses),  a  considerable  number  of  tubes 
must  be  employed  if  any  quantity  of  vaccine  be  desired. 

THE  DIPLOCOCCUS  INTRACELLULARIS  (WEICHSELBAUM), 
on  MENINGOCOCCUS 

in  cases  of  cerebro-spinal  meningitis  is  best  isolated 
from  the  cerebro-spinal  fluid  obtained  by  lumbar  punc- 
ture. A  pure  growth  is  obtained  by  planting  this  upon 
agar  or  blood-serum,  where  it  forms  a  number  of  trans- 
parent colonies,  which  run  together  to  form  a  thin  layer. 
If  cerebro-spinal  fluid  be  not  obtainable,  then  isolation 
must  be  attempted  from  the  nasal  secretion  from  as  high 
up  on  the  septum  and  turbinal  bones  as  is  possible  by 
means  of  the  platinum  loop.  Subcultures  are  best  made 
on  blood-serum.  In  these  cases  careful  differentiation 
from  the  Micrococcus  catarrhalis  and  pseudo-catarrhalis 
cocci  so  commonly  present  in  nasal  mucus  is  necessary. 


58 


VACCINE  THERAPY 


The  points  given   in   the   following    table   are  of   great 

service  : 

TABLE  VI. 


Diplococcus  lutracellularis. 


I.  Colonies  on  agar  soft 
and  sticky,  smooth,  or 
only  finely  granular, 
confluent  only  when 
crowded. 

II.  Cultures    in    broth    are 
generally  turbid. 


III.  Produces  acid  from  mal- 

tose, and  usually  from 
glucose,  galactose,  and 
levulose,  but  not  from 
saccharose. 

IV.  Does     not     agglutinate 

spontaneously  in  emul- 
sions, but  does  with 
the  serum  of  an  animal 
which  has  been  in- 
jected with  the  menin- 
gococcus. 


Micrococcus  Catarrhalis. 


I.  Colonies  on  agar  thicker, 
more  opaque,  coarsely 
granular,  readily  be- 
coming confluent,  and 
of  firm  consistency. 
II.  Cultures  in  broth  usually 
remain  clear,  with  a 
coarsely  granular  de- 
posit at  the  bottom, 
usually  suspended  in  a 
mucus-like  ball. 
III.  Does  not  produce  acid 
from  any  of  these  car- 
bohydrates. 


IV.  Agglutinates  spontane- 
ouslyin  emulsions  even 
of  considerable  dilu- 
tion. 


PREPARATION  OF  THE  EMULSION. 
Having  thus  obtained  a  pure  eighteen-  to  twenty-four- 
hour-old  growth  of  the  organism  on  the  suitable  medium, 
we  now  proceed  as  follows  (the  tubercle  bacillus  alone 
excepted)  :  The  following  are  the  necessary  materials  : 
Aluminium  or  glass  rod  ;  0- 1  per  cent,  solution  of  sodium 
chloride  in  distilled  water,  sterilized  by  boiling  ;  two  small 
strong  Ehrlenmeyer  flasks,  and  three  or  four  small  glass 


PREPARATION  OF  THE  VACCINE  59 

beads,  also  sterilized  ;  a  centrifuge  with  10  c.c.  centrifuge 
tubes  ;  a  sterilizer  which  can  be  maintained  at  any 
temperature  between  55°  and  65°  C.  for  one  to  two  hours  ; 
tricresol ;  a  capillary  pipette,  with  rubber  teat  ;  some 
sterilized  solution  of  2  per  cent,  neutral  sodium  citrate  in 
distilled  water ;  four  glass  slides  ;  Irishman's  stain  ; 
distilled  water  ;  microscope  with  TVinch  oil-immersion 
lens  and  mechanical  stage. 

If  the  culture  tube  do  not  contain  sufficient  water  of 
condensation,  4  or  5  drops  of  the  0-1  per  cent,  saline 
solution  are  now  introduced.  By  means  of  the  aluminium 
rod  the  bacterial  growth  is  emulsified  as  thoroughly  as 
possible. 

The  two  or  three  tubes  are  treated  in  this  way,  a  little 
more  saline  added,  and  the  whole  transferred  to  the  small 
flask  with  two  or  three  glass  beads.  The  tubes  are 
washed  out  with  a  few  drops  of  saline,  which  is  added  to 
the  first  portions.  The  emulsification  of  the  growth  is 
now  completed  by  agitating  the  flask  for  some  minutes, 
the  beads  helping  to  break  up  the  colonies  present.  The 
emulsion,  which  should  measure  about  5  c,c.,  is  now 
transferred  to  one  of  the  centrifuge  tubes,  an  equal 
volume  of  water  being  added  to  the  other  as  counter- 
poise. After  a  few  minutes'  more  or  less  vigorous  centri- 
fugalization,  according  to  the  size  of  the  organism,  the 
emulsion  is  poured  oft  from  the  sediment  into  the  second 
flask,  and  is  ready  for  standardization. 


STANDARDIZATION  OF  THE  VACCINE. 

This  is  carried  out  as  follows  :  One  end  of  a  few  inches 
of  glass-tubing,  -|  inch  in  external  diameter,  is  drawn  out 
into  a  fine  capillary  thread,  which  is  then  cut  off,  giving 


60  VACCINE  THERAPY 

a  total  length  of  6  to  8  inches.  A  rubber  teat  is  fitted 
to  the  larger  extremity,  and  a  mark  made  upon  the 
capillary  thread  about  £  inch  from  the  end.  This  consti- 
tutes the  unit  volume.  The  emulsion  being  ready  to 
hand,  the  finger-tip  is  pricked  on  the  dorsum,  and  a  drop 
of  blood  expressed.  By  gently  compressing  the  rubber 
teat,  and  then  slightly  releasing  the  pressure,  two  or  three 
volumes  of  the  2  per  cent,  citrate  solution  are  sucked  into 
the  capillary  thread  ;  then  a  small  bubble  of  air,  next 
a  volume  of  blood,  then  a  bubble  of  air,  finally  a  volume 
of  the  emulsion.  The  whole  is  then  expelled  on  one  of 
the  clean  glass-slides,  and  carefully  mixed  by  alternately 
sucking  it  up  and  expelling  it  upon  the  slide.  This 
mixing  having  been  thoroughly  carried  out,  the  whole 
is  divided  into  approximately  three  parts,  which  are 
transferred  each  to  a  clean  slide,  and  then  carefully 
and  evenly  spread  by  means  of  the  edge  of  another. 
In  this  way  uniform  smears  are  obtained.  These  are 
allowed  to  dry  in  the  air,  and  then  stained  with  Leish- 
man's  stain  for  five  minutes.  The  slides  are  then  flooded 
with  distilled  water,  which  is  allowed  to  remain  for 
fifteen  minutes  ;  they  are  then  washed  in  distilled  water 
till  pink  in  colour,  and  no  more  blue  escapes  into  the 
water,  and  dried  with  filter-paper. 

They  are  now  ready  for  counting.  By  means  of  a 
blue  grease-pencil  the  two  diameters  at  right  angles  are 
marked  upon  the  ocular  of  the  microscope  so  that  the 
field  is  divided  into  four  quadrants.  The  counting  is 
thereby  greatly  facilitated,  and  is  carried  out  as  follows  : 
The  smear  in  the  slide  is  mentally  divided  up  into  nine 
equal  areas,,  as  in  the  subjoined  figure.  A  whole  field  of 
the  microscope  is  then  counted  at  each  of  the  angles 
as  indicated,  so  that  a  total  of  sixteen  fields  is  counted. 


61 


The  numbers  of  red  blood-cells  seen  in  each  field  are 
set  down  in  one  vertical  column,  the  numbers  of 
organisms  in 
another.  Each 


column  is 
then  added 
up,  so  that 
the  numbers 
of  corpuscles 

and  bacilli  respectively  in  sixteen  microscope  fields  are 
estimated.  This  is  repeated  for  the  second  slide,  and 
the  two  results  added  together.  These  thirty-two 
fields  may  be  assumed  to  give  a  sufficiently  accurate 
count.  We  will  assume  that  600  red  cells  have  been 
counted  and  1,500  bacilli.  Now,  a  cubic  millimetre  of 
blood  contains  5,500,000  red  cells,  and  equal  volumes 
of  blood  and  of  emulsion  were  taken.  A  cubic  millimetre 

5,500,000x1,500 


of    the    emulsion,    therefore   contains 


600 
millimetre, 


or 


or     13,750,000     organisms     per     cubic 
13,750,000,000  per  cubic  centimetre. 

It  being  desirable  to  have  doses  of  125,  250,  500, 
and  1,000  million  bacilli  respectively  contained  in  either 
|  c.c.  or  1  c.c.  of  fluid,  it  now  becomes  necessary  to 
dilute  the  emulsion.  To  obtain  1,000  million  per  c.c. 
it  is  obvious  that  each  1  c.c.  of  the  emulsion  has  to  be 
made  up  to  13-75  c.c.  with  0-1  sterile  salt  solution.  This 
is  accordingly  done,  and  sufficient  tricresol  added  to 
made  a  0-2  per  cent,  solution.  This  is  of  sufficient 
strength  to  inhibit  the  growth  of,  or  even  destroy,  any 
spores  of  air-organisms  which  may  have  gained  ad- 
mittance to  the  emulsion,  and  may  escape  destruction 
in  the  subsequent  sterilization. 


62 


STERILIZATION  OF  VACCINE. 

The  flask  containing  the  emulsion  is  now  placed  in 
a  sterilizer  at  56°  to  60°  C.,  and  maintained  at  that 
temperature  for  one  or  one  and  a  half  hours,  according 
to  the  resistance  of  the  organism  to  heat.  The  lower 
the  temperature  that  can  be  employed  with  safety,  the 
more  potent  is  the  vaccine.  It  is  then  allowed  to  cool, 
and  is  ready  for  the  next  step. 

TUBING  THE  VACCINE. 

Materials  required  :  Sufficient  sterilized  glass  serum- 
bulbs  of  1-5  to  2-0  c.c.  capacity,  in  two  colours — say 
white  and  blue  ;  a  standard  burette,  also  sterilized  and 
graduated  to  TV  c.c.  ;  a  hypodermic  needle  and  2  or 
3  inches  of  thin  rubber-tubing,  also  sterile.  To  the  end 
of  the  burette  the  needle  is  attached  by  means  of  rubber- 
tubing.  The  burette  being  set  up  vertically,  the  tap  is 
closed  and  the  emulsion  poured  in  ;  the  tap  is  then 
opened  till  a  drop  of  fluid  appears.  Into  a  number  of 
the  white  bulbs  1  c.c.  of  emulsion  is  run,  into  others  \  c.c. 
The  former  will  thus  contain  1,000  and  the  latter  500 
million  organisms.  The  ends  are  sealed  off  by  holding 
in  the  tip  of  the  flame  of  a  Bunsen  burner.  A  sufficiency 
of  these  doses  having  been  made,  the  remainder  of  the 
emulsion  is  returned  in  its  flask,  and  3  volumes  of 
0-1  saline  solution,  together  with  sufficient  tricresol  to 
make  it  up  to  0-2  per  cent.,  added.  This  having  been 
thoroughly  shaken  up,  tubing  into  the  blue  bulbs  is 
carried  out  as  before.  One  c.c.  will  now  contain  250 
and  \  c.c.  125  million  organisms.  We  are,  therefore,  in  a 
position  to  administer  doses  of  125  millions  and  any  of 
its  multiples  or  submultiples. 


PREPARATION  OF  THE  VACCINE  63 

The  bulbs  are  set  aside  till  next  day,  when  sterilization 
at  60°  C.  is  again  carried  out  for  one  hour.  These  two 
sterilizations  should  be  quite  sufficient  to  kill  the 
organisms.  Should  there  be  any  doubt,  however,  a 
third  sterilization  may  be  carried  out  on  the  following 
day,  but  is  not  to  be  recommended,  as  the  strength  of 
the  vaccine  may  be  impaired  by  too  prolonged  heating. 

The  bulbs  should  now  be  marked  by  means  of  a  diamond 
pencil  with  the  name  of  the  organism  and  the  number 
contained  in  each  tube.  In  this  way  mistakes  at  any 
subsequent  date  will  be  obviated. 

THE  VARIOUS  FORMS  OF  TUBERCULIN. 

Tuberculin  T.  (Koch,  1890) 

is  a  clear  brownish  fluid,  obtained  by  filtering  through 
a  porcelain  filter  a  glycerine  broth  culture  of  tubercle 
bacilli  which  has  been  evaporated  on  a  water-bath  to 
one-tenth  its  volume. 

Tuberculin  T.R.  (Koch}. 

Young,  highly  virulent  bacilli  are  dried  in  vacua,  and 
then  comminuted  by  machinery.  The  dust  thus  obtained 
is  heated  with  distilled  water,  and  the  mixture  placed  in 
a  centrifuge,  making  4,000  revolutions  per  minute.  In 
this  way  an  opalescent  fluid  (T.O.),  possessing  analogous 
properties  to  the  old  tuberculin,  and  a  deposit  are 
obtained.  The  latter  is  then  emulsified  with  successive 
quantities  of  water,  and  constitutes  the  new  tuberculin, 
or  T.R.,  which  is  sold  in  bottles  containing  2,  and  not, 
as  originally  stated,  10,  milligrammes  of  solid  bacterial 
substance  per  c.c. 


64  VACCINE  THERAPY 

The  occasional  presence  of  living  tubercle  bacilli 
capable  of  multiplication  in  the  new  tuberculin  has  led 
to  occasional  accidents.  Wright  and  Douglas  found 
that  heating  to  60°  C.  for  one  hour  sufficed  to  kill  any 
bacteria  and  did  not  impair  the  tuberculin.  After 
tubing  off  into  appropriate  doses,  it  is,  therefore,  well  to 
thus  sterilize  the  tuberculin  before  administration. 

Inasmuch  as  the  T.O.  thus  obtained  gives  no  pre- 
cipitate with  glycerine,  while  the  T.R.  does,  it  is  held 
that  the  former  contains  those  elements  of  the  bacilli 
which  are  soluble  in  glycerine,  and  are  therefore  similar 
to  those  contained  in  the  old  tuberculin.  The  T.R.,  on 
the  other  hand,  is  supposed  to  be  freed  from  these  dan- 
gerous constituents.  All  the  immunizing  substances  of 
the  T.O.,  according  to  Koch,  are  contained  in  the  T.R., 
and  a  man  immunized  with  T.R.  will  not  react  against 
a  large  dose  of  T.O. 

The  ordinary  T.R.  is  prepared  from  bacilli  of  human 
origin,  and  in  morphology  and  cultural  reactions  con- 
forming to  a  certain  standard. 

A  similar  T.R.,  known  as  P.T.R.  (Perlsucht  T.R.),  is 
prepared  from  bacilli  of  bovine  origin,  which  in  morphology 
and  cultural  reactions  differ  characteristically  from  the 
human  type. 

Bacillary  emulsion  (B.E.)  is  probably  the  most  active 
of  all  the  tuberculin  preparations,  and  contains  5  milli- 
grammes of  bacillary  substance  per  c.c.  It  may  be 
derived  from  bacteria  either  of  the  human  or  bovine  type, 
and  consists  of  the  comminuted  bodies  of  the  bacilli, 
which  are  not  subjected  to  any  process  for  removal  of 
toxin,  in  glycerine  emulsion.  It  therefore  stimulates  the 
formation  of  antitoxic  as  well  as  of  antibactericidal 
substances. 


PREPARATION  OF  THE  VACCINE  65 

Tuberculocidin  (Klebs). 

Klebs,  in  1891,  came  to  the  conclusion  that  the  de- 
leterious substances  contained  in  T.O.  were  of  an  alka- 
loidal  nature.  These  he  endeavoured  to  remove,  and  to 
the  tuberculin  thus  obtained  gave  the  above  name. 


Tuberculosetoxin  (Maksutow). 

Maksutow,  in  1897,  raised  the  objection  to  tuberculin 
that  it  was  prepared  from  bacilli  grown  on  artificial 
culture  media,  and  that  the  chemical  constituents  of 
these  media  and  their  disintegration  products  introduced 
a  complicating  factor.  A  toxin  so  obtained  he  held  was 
not  necessarily  identical  with  the  specific  toxin  of  the 
bacillus.  He  therefore  made  extracts  from  the  tuber- 
culous tissues  of  diseased  guinea-pigs,  and  from  this 
material  obtained  a  tuberculosetoxin  free  from  bacilli, 
and  capable  of  producing  immunity  in  animals  in  about 
three  months. 

Tuberculol. 

Landman,  in  1898,  described  a  preparation  in  which  the 
bacilli  were  extracted  with  normal  saline  solution,  distilled 
water,  and  glycerine  at  progressively  increasing  tempera- 
tures, the  first  extraction  being  made  at  40°  C.,  the  last  at 
100°  C.,  the  different  extracts  being  then  added  together. 
To  this  preparation  he  gave  the  name  '  tuberculol.' 

Bouchard,  at  the  International  Congress  of  Tubercu- 
losis, 1905,  also  described  a  new  form  of  tuberculin, 
which  he  claimed  to  be  bactericidal  in  vitro,  and  immu- 
nizing and  curative  in  man  and  animals. 

5 


66  VACCINE  THERAPY 

Tulase  (Behring,  1905) 

contains  the  somatic  substance  of  the  tubercle  bacillus, 
which  takes  up  the  stain  by  the  Gram  and  Ziehl-Nielsen 
methods.  The  method  of^preparation  is  a  very  compli- 
cated one,  consisting  partly  in  the  treatment  of  the 
bacilli  with  chloral.  It  may  be  administered  intra- 
venously, subcutaneously,  or  by  the  mouth,  and  is 
claimed  to  produce  both  antituberculous  immunity  and 
hypersensibility  to  Koch's  tuberculin.  In  persons  not 
infected  by  tubercle  immunization  by  tulase  is  said  to 
be  produced  after  four  months,  whereas  in  those  already 
infected  response  appears  to  be  more  rapid. 

PREPARATION  OF  COMBINED  VACCINES. 

In  certain  conditions,  such  as  pulmonary  phthisis, 
tuberculosis  of  the  bladder  and  kidneys,  and  bones  and 
joints,  additional  gravity  is  added  to  the  case  when  to 
the  primary  infection  secondary  ones  are  added.  All 
are  familiar  with  the  comparative  ease  with  which  a  case 
of  early  pulmonary  phthisis  or  tubercular  joint  disease 
yields  to  appropriate  treatment,  and  the  difficulty  of 
dealing  with  such  a  case  when  once  staphylococci  or 
streptococci  have  complicated  the  infection.  Occasion- 
ally, it  is  true,  great  improvement  follows  the  adminis- 
tration of  tuberculin  alone,  but  the  best  results  will, 
I  am  convinced,  be  secured  by  either  previously  or 
simultaneously  attacking  the  secondary  infection.  In 
these  instances  it  is,  as  a  rule,  easy  to  ascertain  the  exact 
nature  of  this  infection.  In  bladders  and  kidneys  it  is 
usually  the  Bacillus  coli  communis ;  in  bones  and  joints, 
staphylococci  or  streptococci.  Other  forms  of  bacillary 


PREPARATION  OF  THE  VACCINE  67 

infection  there  are,  however,  such  as  Pyorrhoea  Alveo- 
laris,  Gleet,  and  Chronic  Tracheal  Catarrh,  in  which  it  is 
wellnigh  impossible  to  tell  which  out  of  the  many  dif- 
ferent bacteria  present  are  responsible  for  the  condition. 
The  only  thing  then  to  do  is  to  employ  a  '  combined 
vaccine.'  Details  of  cases  and  results  will  be  found 
later.  At  present  attention  will  be  confined  to  the 
method  of  preparing  such  a  vaccine.  The  first  step  is 
to  take  smears  of  the  discharge.  If  this  be  sputum, 
suitable  lumps  should  be  chosen,  and  washed  repeatedly 
in  sterile  salt  solution  before  spreading  the  films.  These 
are  then  stained  with  methylene  blue  and  by  Gram's 
method,  using  neutral  red  as  counterstain.  Careful  note 
is  made  of  the  organisms  present  as  far  as  possible,  and 
their  relative  numbers  estimated.  Cultures  upon  suitable 
media — best  upon  several,  such  as  upon  agar,  blood-agar, 
and  blood-serum,  and  in  broth — are  also  made,  and  films 
prepared  from  these  after  four,  eight,  twelve,  eighteen, 
and  twenty-four  hours'  incubation,  and  stained  as  before. 
The  identification  of  the  various  organisms  is  thus  made 
more  complete,  and  the  medium  upon  which  the  relative 
proportions  of  the  organisms  detected  in  the  secretion  is 
best  preserved  noted,  as  well  as  the  appropriate  time  of 
incubation.  Sometimes  it  will  be  found  that  one  of  the 
organisms  most  numerous  in  the  original  smears  refuses 
to  grow  in  the  presence  of  the  others.  There  is  then 
nothing  for  it  but  to  plate  out  cultures,  isolate  the  various 
bacteria,  make  fresh  cultures,  and  prepare  the  several 
vaccines  separately,  and  then  mix  them  together.  As  a 
rule,  however,  this  is  unnecessary.  There  is  nearly 
always  one  medium  and  a  certain  duration  of  incubation 
which  will  give  an  emulsion  in  which  the  bacteria  are 
preserved  in  approximately  their  original  proportions. 

5—2 


68  VACCINE  THERAPY 

If  one  organism  be  found  to  outgrow  the  others,  sufficient 
of  it  may  usually  be  removed  from  colonies  by  means  of 
the  platinum  loop  to  re-establish  the  desired  ratio. 

It  must,  however,  be  admitted  that  the  best  and  most 
scientific  method  is  to  plate  out  cultures,  isolate  the 
several  organisms,  omitting  any  non-pathogenic  air 
organisms  which  may  be  present,  and  from  subcultures 
to  prepare  the  several  emulsions,  which  may  be  then 
standardized  and  mixed  in  such  proportions  that  the 
appropriate  initial  dose  of  each  is  secured  in  J  c.c.  of  the 
mixture. 

The  usual  result  of  two  or  three  injections  at  three- 
weekly  intervals  of  such  a  vaccine  is  to  produce  a  most 
marked  reduction  in  the  number  and  variety  of  the 
organisms  to  be  seen  in  films  prepared  from  the  secretion. 
These  may  then  be  dealt  with  by  a  fresh  vaccine  pre- 
pared in  a  similar  manner. 

ADMINISTRATION  OF  THE  VACCINE. 

The  opsonic  index  having  been  taken  and  the  suit- 
ability of  the  case  for  injection  determined,  the  dosage 
must  be  decided  on.  The  average  initial  dose  for  each 
organism  is  given  in  subsequent  pages  ;  it  is  better  to 
err  on  the  side  of  too  small  rather  than  on  that  of  too 
large  dosage.  The  best  site  for  injection  is  in  the 
loose  subcutaneous  tissue  of  the  side.  It  may,  how- 
ever, be  done  in  the  back  or  upper  arm.  Several  little 
points  are  to  be  noted  ;  thus,  no  one  can  predict  how  much 
local  reaction  may  result.  In  flabby  abdominal  walls 
there  is  usually  none.  Five  or  six  injections  may  pro- 
duce none  whatever,  and  the  next  quite  a  considerable 
amount.  A  small  lump  as  large  as  a  walnut  may  be 


PREPARATION  OF  THE  VACCINE  69 

formed,  and  the  skin  reddened.  .  This  may  be  quite 
painful  each  time  the  patient  breathes,  or  coughs,  or 
moves  the  abdominal  wall.  This  result  being  possible, 
it  is  necessary  to  provide  against  it,  and  the  following 
rules  are  useful  :  (1)  Do  not  inject  on  the  side  upon 
which  the  patient  lies  ;  (2)  hi  women  do  not  inject  where 
corsets  are  likely  to  press  ;  (3)  avoid  veins,  and  so  pro- 
duction of  a  hsematoma  ;  (4)  do  not  inject  so  far  for- 
wards that  any  swelling  will  lie  over  the  edge  of  the 
rectus  abdominis  muscle  ;  (5)  remember  that  if  a  large 
fold  of  skin  be  picked  up  and  the  needle  be  pushed  well 
in,  the  inoculum  will  lie,  perhaps,  2  inches  from  the  site 
of  puncture. 

A  very  safe  situation  is,  therefore,  on  the  right  abdo- 
men, about  J  inch  above  the  anterior  superior  spine  of 
the  ilium,  and  about  \  inch  internal  to  it.  If  a  good  fold 
of  skin  be  raised  and  the  puncture  made  at  the  spot 
indicated,  the  inoculum  will  lie  \\  to  2  inches  internal  to 
the  anterior  superior  spine,  and  any  reaction  will  cause 
a  minimum  of  discomfort. 

The  site,  then,  having  been  decided  upon,  the  adjacent 
skin  should  be  well  cleansed  with  warm  soap  and  water, 
followed  by  a  little  2  per  cent,  lysol.  The  neck  of  the 
bulb  is  scratched  with  a  file  and  broken  off.  The  inoculum 
is  then  sucked  up  into  an  ordinary  hypodermic  syringe, 
which  has  been  thoroughly  sterilized.  Any  air-bubbles 
are  expelled,  and  the  needle  inserted  to  nearly  its  full 
length  into  the  fold  of  skin  and  the  vaccine  expelled. 
The  puncture  is  then  closed  with  a  little  collodion. 
These  aseptic  precautions  may  be  considered  hardly 
necessary,  but  infection  from  the  skin  or  a  dirty  needle 
has  been  known  to  occur.  No  care  is  too  great  to  take 
to  obviate  such  an  unhappy  result. 


70  VACCINE  THERAPY 

ADMINISTRATION  OF  VACCINES  BY  THE  MOUTH. 

Patients,  even  the  best  of  them,  certainly  begin  to  get 
weary  after  a  time  of  subcutaneous  inoculations,  especially 
at  diminishing  intervals.  Latham1  has  advocated  their 
oral  administration.  He  states  that  vaccines,  if  given  on 
an  empty  stomach,  either  with  normal  saline  or  horse 
serum  (about  10  c.c.  in  either  case),  undergo  perfect 
absorption,  and  produce  exactly  similar  results  to  when 
introduced  hypodermically.  Favourable  results  were  re- 
ported in  staphylococcal,  streptococcal,  pneumococcal, 
and  tubercular  infections,  the  ordinary  dosages  being 
employed  except  in  the  tuberculous  cases,  where  such 
large  doses  were  employed  at  such  short  intervals  as 
certainly  are  not  free  from  considerable  danger  if  ab- 
sorption be  complete.  This  method  of  administration 
cannot  yet  be  said  to  have  had  its  utility  satisfactorily 
established  ;  probably  it  will  be  found  to  be  of  distinct 
value,  but  necessarily  not  so  reliable  as  the  subcutaneous 
method. 

1  Proceedings  of  the  Royal  Society  of  Medicine,  1908,  vol.  i.,  Xo.  6. 


CHAPTER  V 

THE    OPSONIC    INDEX   IN    HEALTH   AND    DISEASE  :    ITS 
VALUE  IN  DIAGNOSIS,  PROGNOSIS,  AND  TREATMENT 

THE  OPSONIC  INDEX  IN  HEALTH. 

BULLOCH  determined  the  indices  towards  the  tubercle 
bacillus  for  forty-four  medical  students  and  forty  hospital 
nurses,  all  presumably  free  from  tubercular  infection. 
The  results  showed  a  variation  from  a  minimum  of  0-8 
to  a  maximum  of  1-2  as  compared  with  an  index  of  unity 
for  the  serum  of  himself.  The  average  for  the  whole 
eighty-four  cases  was  0-96.  Urwick  in  twenty  cases 
obtained  an  average  of  1-006,  and  Lawson  and  Stewart 
in  twenty-five  cases  an  average  of  1-0. 

The  tuberculo-opsonic  index  of  the  average  healthy 
individual  should  therefore  lie  between  0-8  and  1-2, 
approximating  as  closely  as  possible  to  1-0. 

The  mean  staphylococcal  opsonic  index  of  twenty-five 
healthy  adults  was  found  by  Bulloch  to  be  1-0  ;  other 
observers  have  obtained  a  like  result,  the  variation  being, 
as  a  rule,  less  than  in  the  case  of  the  tubercle  bacillus. 
Numerous  observations  with  other  organisms  show  that 
the  same  holds  true  in  each  case  ;  it  may  therefore  be 
assumed  that  the  opsonic  index  for  any  organism  of  the 
serum  of  the  average  healthy  person  varies  only  between 
narrow  limits,  the  minimum  being  0-8  and  the  maximum  1-2. 

71 


72 


VACCINE  THERAPY 


The  index  has  also  been  shown  by  Unvick  to  be  prac- 
tically constant  from  day  to  day  in  healthy  subjects.  He 
gives  the  following  figures  for  the  tuberculo-opsonic 
indices  of  the  serum  of  a  healthy  individual  as  compared 
with  his  own  on  various  dates  : 


TABLE  VII. 


November    1  = 

»  8  = 

12  = 

30  = 


M 
1-0 
1-0 
1-15 


December   5     = 

= 

13  = 

14  = 
19     = 


09 
09 
1-0 
1-0 
1-0 


Certain  factors  do,  however,  produce  very  slight 
changes  in  the  index.  French,  for  instance,  has  found  that 
vigorous  exercise,  such  as  a  twelve-mile  walk  undertaken 
by  a  healthy  person  of  sedentary  habit,  will  sometimes 
cause  a  rise  from  1-0  to  1-2  or  1-3  on  the  following  da}'. 
Ellett1  showed  that  this  positive  phase  was  preceded  by 
a  negative  one.  I  myself  have  noticed  a  diurnal  variation 
very  similar  to  that  exhibited  by  the  temperature  chart. 
This  is  well  seen  in  the  following  table,  the  organism 
employed  being  the  bacillus  of  Friedlander : 


TABLE  VIII. 


Date. 

8a.m. 

9  a.m. 

11  a.m. 

4  I1'™'       n^ght" 

3  a.m. 

Mav  15,  1906 

1 

1-06 

1-14 

May  18,  1906  .  . 

1 

1-11 

1-20 

— 

May  29,  1906 

1 

1-08 

1-08       1-2         1- 

26 



June  6,  1906    .  . 

1 

— 

1-07                    1- 

18 

10 

June  12,  1906  .  . 

1 

MO 

1- 

14 

— 

British  Medicnl  Journal,  July  21,  1907. 


OPSONIC  INDEX  IN  HEALTH  AND  DISEASE     73 

From  this  it  would  appear  that  the  index  is  at  a  maxi- 
mum between  4  p.m.  and  midnight,  being  raised  by  the 
active  processes  of  life,  a  fall  to  unity  rapidly  occurring 
after  retirement  to  bed.  Abstinence  from  food  or  exces- 
sive exercise  did  not  appear  to  have  any  immediate  effect 
in  the  production  of  a  lowered  index. 

Charteris1  made  observations  upon  the  opsonic  index 
towards  staphylococcus  and  B.  typhosus  of  the  blood 
of  a  man  undergoing  a  fast  of  fourteen  days,  during 
which  no  food  at  all  was  taken.  From  counts  made  upon 
thirty  cells  he  concluded  that  the  index  remained  practi- 
cally unaffected  by  the  fast. 


THE  OPSONIC  INDEX  IN  INFANCY. 

Wells  and  Freeman2  have  made  a  considerable  number 
of  observations  upon  the  opsonic  index  towards  various 
organisms  of  the  blood  of  infants  from  birth  up  to  one 
year  of  age.  They  found  practically  a  normal  index  at 
birth,  but  that  it  was  subject  to  very  great  fluctuations 
from  time  to  time,  and  concluded  : 

1.  That  a  low  opsonic  index  is  not  diagnostic  in  children 
under  one  year  old. 

2.  That  a  low  opsonic  index  in  infants  is  not  inconsis- 
tent with  health,  and  that  a  child  may  be  thriving  well 
with  a  declining  index. 

3.  That   the   antibacterial  defence   in  infants   cannot 
depend  upon  the  opsonic  content  of  the  serum. 

4.  That  as  regards  opsonic  index  the  healthy  breast- 
fed  infant   possesses   no   apparent   advantage   over   the 
healthy  artificially-fed  child. 

1  Lancet,  September  7,  1907,  p.  685. 

2  Practitioner,  May,  1908,  p.  635. 


74 


VACCINE  THERAPY 


THE  OPSONIC  INDEX  IN  DISEASE. 

1.  In  Tubercular  Injections. — Wright,  in  his  earlier 
experiments  upon  localized  tubercular  infections,  found 
a  general  lowering  of  the  opsonic  index  below  unity.  In 
a  series  of  seventeen  cases,  exclusive  of  pulmonary 
phthisis,  he  found  variations  from  0-4  to  0-85,  with  an 
average  for  the  seventeen  of  0-  64. 

Bulloch  investigated  the  indices  of  150  sufferers  from 
lupus  in  all  stages,  from  very  mild  cases  to  old  intractable 
ones  of  even  forty  years'  standing.  Seventy-five  per  cent, 
of  the  cases  had  indices  below  0-8,  while  the  average  for 
the  150  cases  was  0-75,  distributed  as  follows  : 

TABLE  IX. 


Opsonic  Index. 

Number  of  Cases. 

Percentage. 

Between  0-2  and  0-3 

3 

2-0 

03 

04       .. 

3 

20 

04 

0-5 

21 

14-0 

0-5 

06 

29 

19-6 

06 

0-7 

33 

22-0 

0.7 

0-8 

22 

14-8 

0-8 

0-9 

18 

120 

0-9 

1-0 

7 

4-6 

1-0 

1-4      .. 

14 

9-3 

In  chronic  cases  of  surgical  tuberculosis,  such  as  of 
the  joints,  kidneys,  bladder,  or  glands,  it  appears  to 
be  generally  low,  an  average  of  0-6  being  obtained 
by  Bulloch  in  eleven  cases,  and  of  0-8  in  nine  cases 
by  French. 

Lawson  and  Stewart  made  between  2,000  and  3,000 
observations  upon  cases  of  apyrexial  phthisis,  and  found 
the  index  to  be  always  below  1-0,  varying  from  0-5  to  1/0. 

Urwick    examined    thirty-three    cases    of    pulmonary 


OPSONIC  INDEX  IN  HEALTH  AND  DISEASE      75 


tuberculosis  in  all  stages.  In  twenty-five  he  found  an 
index  above  1-0,  even  as  high  as  2-6  ;  in  seven  an  index 
below  1-0  ;  and  in  one  case  the  index  was  1*0. 

EFFECT  OF  EXERCISE  UPON  TUBERCULO-OPSONIC  INDEX 
IN  CASES  OF  PHTHISIS. 

These  variable  results  were  explained  by  Meakin  and 
Wheeler,1  who  studied  the  index  at  various  times  of  the 
day  in  tubercular  patients  who  were  undergoing  sana- 
torium treatment,  some  of  whom  were  taking  walking 
exercise  and  others  not ;  specimens  of  blood  were  taken 
at  6  a.m.,  9  a.m.,  noon,  and  1  p.m.  If  the  patient  was 
capable  of  taking  exercise,  this  was  done  between  9  a.m. 
and  noon  ;  between  noon  and  1  p.m.  rest  was  taken  in  a 
long  chair. 

The  results  of  some  of  their  observations — five  upon 
patients  taking  exercise,  and  three  not — are  shown  in  the 
adjoined  charts  : 

MEAKIN  AND  WHEELER.    WALKING  CASES. 
CHART  II. 

am. 


Index  G 

16 


8 


a.m. 
9        to 


II 


12 


I 


15 


13 

12- 

II 

10 

09 


T- 


z 


99-1 


7 


Case  No.  1.     Walking.     September  18. 
1  British  Medical  Journal,  November  25,  1905,  p.  1396. 


76 


VACCINE  THERAPY 


CHART  III. 


6          7          8          9          10         II         12         I 


T-98-7 


Case  No.  2.     C.  T.     Walking.     September  27. 


6          7 


CHART  IV. 

a.m.  p.m. 

8          9          10         II         12          I 


Index                            T-975                                  T.g 

i  r\ 

> 

X 

~^s 

^^ 

•«*^. 

/ 

1  U 

/ 

^"•^, 
T 

996 

0'3 
n  B 

y 

Case  No.  3.     W.  L.     Walking.     September  28,  29. 


CHART  V. 
Index   676          9anUK)         II          12         1PJ" 


Id 
17 

/ 

1  1 

T- 

96-2 

*-  

•^^^ 

7 

1  fl  —  i 

^ 

/ 

500 

n-fl 

Case  Xo.  4.     R.  C.     Walking.     October  11. 


OPSONIC  INDEX  IN  HEALTH  AND  DISEASE      77 


Index  6       7 
15 


CHART  VI. 

a.m. 
8         9         10         II 


p.m. 
12          i 


14 
13 
12 
II 
10 


T-977 


Case  No.  5.     H.  M.     AValking.     September  16. 


MEAKIN  AND  WHEELER.     RESTING  CASES. 

CHART  VII. 

a.nv  nm 

Index  e        7       8       a       10       H       12        r 

II 


0* 
0-8 

07 
06 


99-1 


T-197-7 


i993 


Case  No.  5.     H.  M.     Resting.     October  1. 


CHART  VIII. 

a.m.                                  P.I 
Index  6        7        8        9        10        ii        12        i 

'I 

in 

^£ 

09- 

A.ft 

• 

Case  No.  6.     H.  B.     Resting.     September  18. 


78 


VACCINE  THERAPY 


CHART  IX. 

Index  e       7       a       9""  to       n       n       ipm 

ii 

l-O  - 

^^*** 

0-8 
no 

Case  Xo.  7.     D.  H.     Resting.     October  4. 

It  will  be  observed  that  in  all  the  walking  cases  except 
one  a  much  higher  index  was  recorded  at  1  p.m.  than  at 
9  a.m.,  and  that  this  rise  bears  no  obvious  relation  to  rise 
of  temperature,  whereas  in  resting  cases  the  index  is  prac- 
tically constant,  and  either  at  or  below  unity  throughout 
the  day.  This  is  taken  to  indicate  that  in  walking 
cases  there  occurs  a  process  of  auto-inoculation  by  ab- 
sorption of  extremely  minute  doses  of  tubercular  toxin 
by  the  very  vascular  lung  tissue.  How  minute  the  dose  is, 
the  shortness  of  the  negative  phase  (two  or  three  hours) 
clearly  indicates.  The  process  thus  exactly  resembles  the 
succession  of  negative  and  positive  phases  which,  as  we 
shall  see,  is  induced  by  a  series  of  tuberculin  injections. 

Confirmation  of  this  view  is  afforded  by  the  like  results 
which  we  shall  see  later  are  produced  by  surgical  manipu- 
lation of  a  tubercular  joint.  It  would  thus  appear  to  be 
generally  true  that  in  pulmonary  phthisis — 

The  index  is  above  1  in  slight  early  cases. 
The  index  is  variable  in  acute  cases. 
The  index  is  below  1  in  chronic  cases. 

In  acute  cases  there  may  be  either  a  constant  high 
index,  where  the  body  is  making  every  effort  to  cope 
with  the  invaders  and  the  conditions  are  favourable  ;  or 
fluctuating,  where  auto-inoculation  is  occurring — not,  as 


OPSONIC  INDEX  IN  HEALTH  AND  DISEASE      79 

Wright  suggests,  with  too  large  or  badly  interspaced 
doses,  but  with  infinitesimally  small  ones,  so  that  negative 
and  positive  phases  are  alike  of  short  duration,  though 
full  amplitude  ;  or,  finally,  it  may  be  constantly  below 
unity,  if  such  auto-inoculations  be  prevented. 

In  tubercular  infections  of  the  eyeball,  uncomplicated 
by  tuberculosis  elsewhere,  the  index  is  usually  high. 
Thus,  a  case  of  tubercular  iritis  had  an  index  of  1-3,  a  case 
of  keratitis  an  index  of  1-5.  A  third  case,  in  which 
tubercular  keratitis  and  iritis  were  complicated  by 
tubercular  cervical  and  mesenteric  glands  and  by  peri- 
tonitis, had,  on  the  other  hand,  an  index  of  0-4.  As  will 
be  mentioned  later,  all  eye  infections,  whether  acute  or 
chronic,  are  usually  attended  by  high  opsonic  index. 
The  explanation  of  this  is,  I  think,  fairly  obvious.  The 
circulation  of  the  eyeball  is  so  poor  and  the  infection  so 
localized  that  the  very  minute  doses  of  toxin  absorbed  act 
exactly  like  repeated  injections  of  infinitesimally  small 
doses  of  tuberculin  —  so  small  that  the  protective 
mechanism  of  the  body  is  not  exhausted.  That  chronic 
cases  do  not  get  well  with  this  high  index  is,  again,  prob- 
ably due  to  the  poor  circulation,  and  consequently  to  the 
small  amount  of  opsonin  brought  to  the  part. 

Eyre  has  observed  that  broken-down  phlyctenules  may 
be  starting-points  for  tuberculosis  of  the  conjunctiva, 
while  Wright,  in  his  earlier  experiments,  noticed  that 
occasionally  phlyctenules  developed  in  patients  under- 
going inoculations  with  tuberculin.  Nias  and  Paton1 
accordingly  investigated  the  tuberculo-opsonic  index  in 
a  series  of  twenty  cases  of  early  phlyctenular  conjunc- 
tivitis, employing  five  cases  of  other  forms  of  conjunc- 
tivitis as  controls.  They  found  striking  variations  from 

1  Trans.  Ophth.  Soc.,  November  9,  1907. 


80  VACCINE  THERAPY 

the  normal  in  the  indices  of  the  cases  of  phlyctenular 
conjunctivitis,  and  practically  normal  indices  in  the  other 
forms.  The  author  has  obtained  similar  results,  but  it 
must  not  be  lost  sight  of  that  phlyctenules  usually  make 
their  appearances  in  definitely  tubercular  subjects,  and 
that  the  disturbance  of  the  index  is  probably  in  the  major 
part  due  to  infected  glands,  lungs,  bones,  or  joints. 


IN  OTHER  INFECTIONS. 

2.  (a)  In  Acute  Cases. — What  has  been  said  of  pulmonary 
phthisis  holds  equally  for  other  organisms.  When  the 
body  is  making  a  satisfactory  immunizing  response,  the 
index  may  be  maintained  at  a  constant  high  level  and 
above  normal ;  when  auto-inoculations  are  occurring,  the 
index  will  be  fluctuating  ;  while  in  acute  cases,  where  the 
immunizing  machinery  is  in  default,  the  index  will  be  low. 

(b)  In  Chronic  Cases. — Here  the  index  is  almost  uni- 
formly low.  Should,  however,  an  auto-inoculation  occur, 
then  an  immunizing  response  may  be  elicited,  and  the 
index  be  raised  above  normal. 

Da  Costa1  studied  the  opsonic  index  towards  Staphy- 
lococcus  aureus  in  twenty-two  cases  of  diabetes.  Sixteen 
of  these  were  cases  of  true  diabetes  mellitus,  and  all 
showed  subnormal  indices,  varying  between  0-34  and  0-72, 
the  average  being  0-62.  The  liability  of  diabetes  to  boils 
and  carbuncles  is  thus  explained.  Four  cases  of  diabetes 
insipidus  had  indices  between  0-8  and  0-9,  and  two  of 
transient  glycosuria  had  indices  of  0-  8  and  0-  9. 

C.  J.  Shaw2  determined  the  indices  in  fifteen  insane 

1  American  Journal  of  Medical  Science,  July,  1907,  p.  57. 

2  Journal  of  Mental  Science,  January,  1908,  p.  57. 


OPSONIC  INDEX  IN  HEALTH  AND  DISEASE      81 

patients  towards  the  tubercle  bacillus,  Bacillus  coli  com- 
munis,  Staphylococcus,  and  M.  rheumaticus.  The  number 
of  cells  observed  was  never  more  than  fifty,  and  his 
figures  do  not  appear  very  convincing,  but  he  concluded 
that  in  the  insane  the  index  to  the  above  organisms  is 
generally  lower  than  in  the  sane,  and  the  amount  of 
variation  greater.  From  consideration  of  the  indices  he 
deduced  that  the  acutely  mentally  affected  are  more 
liable  to  organismal  infection  than  more  chronic  cases,  but 
that  the  latter  have  less  resisting  power  than  the  sane. 

THE  EFFECT  OF  MENSTRUATION  UPON  THE  INDEX  IN 

INFECTED  CASES. x 

An  important  point  to  remember  in  connection  with  a 
female  infected  by  any  organism  is  that  menstruation 
produces  a  very  marked  lowering  of  the  index  to  that 
organism — an  effect  which  may  begin  a  day  or  two  before 
the  period  and  persist  for  a  day  or  two  after  ;  the  fall  and 
rise,  once  initiated,  move  with  great  rapidity.  It  is, 
however,  stated  that  in  non-infected  females  there  is  a 
general  depression  of  the  opsonic  index  to  all  organisms  ; 
this  statement  needs  confirmation. 

THE  OPSONIC  INDEX  AS  AN  AID  TO  DIAGNOSIS. 

1.  In  Cases  of  Supposed  Tuberculosis. — It  has  been 
mentioned  that  the  index  to  the  tubercle  bacillus  of 
the  sera  of  healthy  subjects  varies  between  0-8  and  1-2. 
The  important  question  now  presents  itself  as  to  how 
we  are  to  regard  an  index  which  does  not  lie  within 
these  limits.  Does  it  mean  that  infection  has  already 
taken  place,  or  merely  that  the  person  is  predisposed 

1  French,  Practitioner,  July,  1906. 

6 


82  VACCINE  THERAPY 

to  it  ?  That  a  low  index  always  means  the  former  of 
these  alternatives  is  certainly  not  the  case,  as  is  shown 
by  the  following  instance  :  Dr.  Eyre,  while  directing  the 
work  of  the  Commission  on  Mediterranean  Fever  in 
Malta,  contracted  the  disease  severely.  After  a  short 
interval  it  was  found  that  his  index  to  the  tubercle  bacillus, 
which  was  known  to  be  normal  before  his  departure  from 
England,  was  below  0-4.  It  remained  at  this  low  level  for 
several  weeks,  and  only  slowly  returned  to  normal.  There 
never  was  any  evidence  soever  of  his  having  been  infected 
by  tubercle.  A  similar  effect  was  also  noticed  in  the 
case  of  Dr.  C.  Pryce  Jones  after  contracting  Malta  Fever. 
It  is  probable  that  a  low  index  precedes  infection,  and 
is  due  either  to  an  acquired  or  hereditary  inability  to 
elaborate  the  chemical  protective  substances  of  the  body. 
It  is  possible  that  a  fall  in  these  bacteriotropic  substances, 
which  is  local  and  not  general,  will  suffice  to  determine 
infection  in  certain  cases.  As  we  have  seen,  a  lowr  index 
is  the  rule  in  chronic  localized  infection ;  and  in  any  case 
of  supposed  tuberculosis  where  a  low  index  is  found, 
especially  in  the  instance  of  a  patient  not  coming  from 
tubercular  stock,  and  where  clinical  appearances  are 
compatible  with  such  a  diagnosis,  tuberculosis  is  highly 
probable.  It  must  not  be  forgotten  that  a  depression  of 
index  may  persist  for  a  long  time  after  an  infection  is 
supposed  to  have  been  cured.  Thus,  in  fourteen  picked 
cases  of  sanatorium  '  cures  '  of  phthisis  in  its  early  stages, 
Bulloch1  found  indices  varying  between  0-4  and  0-86. 
Lawson  and  Stewart2  examined  the  indices  of  twenty-five 
such  cases.  In  five  of  these  it  was  found  to  lie  between 
1-1  and  0-9;  in  the  other  twenty  it  was  0-8  or  under. 

1  Lancet,  December  2,  1905,  p.  1603. 
3  Ibid.,  December  9,  1905,  p.  1683. 


OPSONIC  INDEX  IN  HEALTH  AND  DISEASE     83 

Consideration  of  these  results,  taken  in  conjunction  with 
the  extreme  frequency  with  which  indications  of  healed 
tuberculosis,  either  of  bronchial  glands  or  lungs,  are 
found  in  autopsies  upon  those  never  recognized  as  tuber- 
cular subjects  while  alive,  tends  strongly  to  support  West's 
view  that  all  cases  in  which  low  indices,  not  explicable  by 
such  considerations  as  were  noted  in  Chapter  I.,  are  found 
are  instances  either  of  cured  or  active  tuberculosis.  On 
the  other  hand,  an  abnormally  high  index — 1-3  or  over — 
is  probably  almost  always  asign  of  active  infection. 

Reliance  should  not,  however,  be  placed  upon  a  single 
determination  of  the  index  ;  two  at  least  are  always  ad- 
visable. Should  these  not  agree,  then  a  series  should 
be  done  before  a  definite  conclusion  is  arrived  at.  Con- 
tinual variations  certainly  indicate  active  infection  and 
a  succession  of  auto-inoculations.  Per  contra,  the  non- 
occurrence  of  a  high  or  fluctuating  index  in  patients 
acutely  ill  is  very  strong  evidence  against  a  diagnosis  of 
tuberculosis,  and  lends  support  to  such  alternative  diag- 
noses as  malignant  disease  of  the  lung,  chronic  bronchitis 
and  emphysema,  bronchiectasis,  general  debility,  or 
gonorrhoeal  arthritis. 

An  abnormal  index  will  assist  in  discriminating  such 
conditions  as — 

Tuberculous  kidney  from  malignant  kidney  or  renal  calculus. 
Addison's  disease  from  pernicious  anaemia. 
Tubercular  peritonitis  from  malignant  peritonitis. 

laryngitis  from  laalignant  laryngitis. 

pleurisy   from   malignant  and  other   forms   of 
pleurisy. 

joints  from  syphilitic  and  gonorrhoeal  joints. 

adenitis  from  Hodgkin's  disease. 

endocarditis  from  fungating  and  other  forms  of 
endocarditis. 

keratitis  and  iritis  from  syphilitic  and  rheumatic. 

6—2 


84  VACCINE  THERAPY 

Tubercular  epididymorchitis  from  syphilitic,  adenomatous, 

or  malignant  forms, 
cystitis    from    that    due   to  calculi,    tumours, 

enlarged  prostate,  etc. 
,,  salpingitis  from  gonorrhceal. 

ovary  from  malignant  or  cystic, 
endometritis  from  malignant,  etc. 
Lupus  from  syphilis  or  rodent  ulcer. 

2.  In  Other  Cases. — Opsonic  index  determinations  have 
been  shown  in  numerous  instances  to  be  of  the  utmost 
value  in  the  investigation  of  infections  of  doubtful 
nature.  Thus,  Houston  and  Rankin1  demonstrated  their 
great  value  in  the  diagnosis  of  suspected  cases  of  cerebro- 
spinal  meningitis,  in  which  the  index  is  always  high,  and 
in  the  differentiation  of  the  true  form  of  this  disease  from 
posterior  basic  meningitis. 

In  three  cases  oi  suspected  non-specific  urethritis 
during  the  past  year,  the  author  has  been  enabled  to  make 
a  definite  diagnosis,  and  to  exclude  the  gonococcus — 
rightly,  as  subsequent  events  proved.  The  differentia- 
tion of  an  acutely  rheumatic  or  gonococcal  joint  from  one 
infected  by  other  pyogenic  cocci  is  greatly  facilitated, 
and  the  correct  diagnosis  of  the  infecting  agent  in  septi- 
caemic  cases  where  no  organisms  can  be  isolated  from  the 
blood  rendered  possible. 

A  study  of  the  opsonic  index  in  typhoid  fever  may  well 
prove  especially  productive  of  valuable  results,  and 
enable  a  diagnosis  to  be  established  earlier  than  is  now 
possible  by  any  other  means.  The  careful  study  of 
Wright  and  his  co-workers2  upon  the  artificial  production 
of  auto-inoculations  has  rendered  available  a  method  of 
extreme  value  for  determining  whether  an  infective  focus 
has  completely  healed  or  merely  lies  dormant. 

1  British  Medical  Journal,  November  16,  1907. 

2  Lancet,  vol.  ii.,  1907,  p.  1217. 


OPSONIC  INDEX  IN  HEALTH  AND  DISEASE     85 


SPECIAL  METHODS  or  EMPLOYING  THE  OPSONIC  INDEX 
IN  DIAGNOSIS. 

The  first  method  depends  upon  the  artificial  production 
of  an  auto-inoculation,  and  is  especially  applicable  to 
tuberculosis  and  other  diseases  of  joints.  The  index  is 
taken  ;  passive  movement  of  the  joint  is  then  performed 
by  the  surgeon,  and  fresh  determinations  of  the  index 
done  after  three,  six,  twelve,  and  twenty-four  hours. 
Should  infection  not  be  present,  minimal  variations  in 
the  index  will  be  found  ;  but  should  it  be  present,  the 
production  of  definite  negative  and  positive  phases  will 
be  evidenced.  The  negative  phase  may  be  fully  pro- 
duced within  three  hours  or  may  be  absent. 

The  adjoined  chart  shows  the  effect  produced  in  a  case 
of  doubtful  tuberculosis  of  the  hip  in  a  child  six  years 
old: 


Before 
Manipulation 

Index 
it 


CHART  X. 

hours  after 

9        12        15         18 


24 


Ample  confirmation  of  the  diagnosis  was  thus  secured. 

The  second  method  is  of  wider  applicability.  A  small 
dose  of  T.R.  (0-00002  to  0-00004  c.c.)  is  given,  and  the 
index  estimated  daily. 


86  VACCINE  THERAPY 

In  healthy  subjects  the  negative  phase,  if  present  at 
all,  is  of  very  slight  amplitude  and  short  duration,  last- 
ing, as  a  rule,  for  only  a  few  hours.  The  positive  phase 
resembles  the  negative,  and  the  limit  of  fall  and  rise  in 
the  index  rarely  exceeds  0-  2  or  0-  3.  Lawson  and  Stewart l 
found  no  negative  phase,  but  a  rise  in  one  instance  from 
1-0  to  2-1  within  a  few  hours.  In  infection,  on  the  con- 
trary, a  much  more  pronounced  fall  and  rise  are,  as  a  rule, 
obtained  ;  the  negative  phase  may  last  for  days,  or  even 
a  fortnight,  and  the  crest  of  the  positive  phase  be  not 
attained  for  one  to  three  weeks.  Inasmuch  as  occasion- 
ally no  negative  phase  is  produced  in  cases  undoubtedly 
tubercular,  failure  to  obtain  a  negative  phase  does  not 
entirely  put  the  diagnosis  of  tubercle  out  of  consideration. 
A  third  method  is  the  employment  of  the  original  tuber- 
culin in  doses  insufficient  to  produce  the  acute  disturb- 
ances originally  obtained.  Dodds2  reported  the  effect 
of  injections  of  T.O.  in  doses  containing  1  milligramme 
of  solid  substance  upon  the  opsonic  index  in  five  doubtful 
cases  of  phthisis,  and  in  one  certain  case  exhibiting 
bacilli  in  the  sputum.  In  this  latter  instance  the  index 
before  injection  was  0-7  ;  twelve  hours  after  injection  of 
0-5  milligramme  of  T.O.  the  index  =1-1  ;  upon  the  fifth 
day  it  had  fallen  to  0-9.  Of  the  other  five  cases,  in  four 
the  index  was  normal,  and  remained  so  after  injection  of 
1  milligramme  of  T.O.  Of  these,  three  were  cases  of  old 
pneumococcal  pleurisy,  with  chronic  cough  for  months  ; 
the  fourth  had  a  chronic  cough.  In  the  fifth  case  the 
index  fell  from  1-0  to  0-7,  and  rose  next  day  to  1-4.  He 
had  a  phthisical  family  history,  and  had  had  pleurisy  six 

1  Eclin.  Med.-Chir.  Trans.,  November  1,  1905.     Proc.  Royal  Med.- 
Chir.  Soc.,  November  28,  1905. 

2  British  Medical  Journal,  July  7,  1906,  p.  22. 


OPSONIC  INDEX  IN  HEALTH  AND  DISEASE     87 

years  previously,  with  persistent  subsequent  cough  ;  his 
sputum  was  streaked  with  blood,  and  occasional  night 
sweats  were  present.  In  this  case  the  diagnosis  of  phthisis 
was  held  to  be  confirmed. 

A  fourth  method  depends  upon  the  fact,  already  noted, 
that  in  females  infected  by  an  organism  the  onset  of 
menstruation  initiates  a  very  marked  fall  in  the  index 
towards  that  organism  ;  the  cessation  as  pronounced  a 
rise.  If,  therefore,  a  female  be  suspected  of  tuberculosis, 
determinations  of  the  index  a  couple  of  days  before  the 
onset,  towards  the  end  of  the  period,  and  two  or  three  days 
after  should  reveal  marked  negative  and  positive  phases. 

In  two  cases  of  severe  recurrent  episcleritis  which  is 
by  some  eye  pathologists  considered  to  be  of  tubercular 
origin,  I  utilized  this  method.  In  the  first  the  tuberculo- 
opsonic  index  before  menstruation  was  O96,  and  during 
menstruation  0-93  ;  tuberculin  injections  were  therefore 
not  advised. 

In  the  second  case  it  was  T26  before  menstruation,  and 
1-28  during  the  period.  No  other  clinical  evidence  of 
tubercle  could  be  found,  and,  as  before,  despite  the  some- 
what high  index,  tuberculin  injections  were  held  to  offer 
slight  chance  of  improvement.  As,  however,  the  patient 
came  from  tubercular  stock,  and  wished  to  avail  herself  of 
every  chance,  four  injections  were  given  at  three  weekly  in- 
tervals, but  without  producing  the  slightest  improvement. 

A  fifth  method,  whereby  the  presence  of  a  suspected 
infection  can  be  established,  has  been  devised  by  Peel 
Ritchie,1  and  should  prove  especially  useful  in  cases 
where  an  index  upon  the  border-line  of  the  normal — 
say  0-8 — has  been  obtained  by  the  usual  method.  If  the 
serum  of  an  infected  individual  be  compared  with  a 
1  Lancet,  November  16,  1907,  p.  1419. 


88  VACCINE  THERAPY 

normal  serum,  not  only  undiluted,  but  also  when  diluted 
with  five  volumes  of  normal  saline,  it  will  be  found  that  the 
index  is  lower  for  the  diluted  than  for  the  undiluted 
sample.  But  if  the  two  sera  be  treated  with  a  thick 
suspension  of  a  bacterium  other  than  that  with  which  the 
individual  is  infected,  and  the  index  towards  the  infecting 
organism  be  determined  for  the  diluted  and  undiluted 
sera,  a  different  result  is  obtained  ;  the  serum  of  the  in- 
fected individual  will  now  show  a  much  higher  relative 
value  than  before.  Thus  the  serum  of  a  certain  tuber- 
culous person  was  compared  with  that  of  a  healthy  one 
and  found  to  have  an  index  of  0-73  ;  both  sera  were  then 
diluted  five  times  with  normal  saline,  and  the  index 
found  to  be  0-53.  The  phagocytic  power  towards  the 
tubercle  bacillus  was  then  redetermined  for  the  diluted 
sera,  a  considerable  amount  of  a  culture  of  Bacillus  coli 
communis  being  also  added  to  the  phagocytic  mixture. 
The  tuberculo-opsonic  index  of  the  diluted  serum  of  the 
infected  individual  was  now  found  to  be  1-31. 

This  depends  upon  the  fact,  as  we  have  seen,  that  in  the 
blood  of  an  infected  individual  opsonin  specific  against 
the  infecting  organism  is  elaborated,  and  it  is  the  amount 
of  specific  opsonin  which  is  alone  estimated  by  this  latter 
procedure. 

For  tubercle  estimations  Ritchie  advises  the  addition 
of  Bacillus  coli  communis  to  absorb  the  non-specific 
opsonin,  and  for  other  estimations  absorption  with  the 
aid  of  tubercle  bacilli.  The  relative  rise  is  rarely  less  than 
0-2,  and  is  often  very  striking.  Ritchie  employed  this 
method  in  150  cases  of  varied  infections  with  striking 
success.  Failure  occurred  in  only  eleven  cases,  which 
were  all  tubercular ;  the  explanation  of  this  will  be  given 
later  (see  p.  104). 


OPSONIC  INDEX  IN  HEALTH  AND  DISEASE     89 

THE  OPSONIC  INDEX  AS  AN  AID  TO  PROGNOSIS. 

1.  In  Pulmonary  Phthisis. — It  is  beyond  question  that 
the  cases  of  pulmonary  phthisis  which  do  worst  are  the 
pyrexial  ones,  and,  as  we  have  seen,  these  exhibit  violent 
fluctuations  in  the  index.  Rest  in  bed  steadies  the  tem- 
perature and  opsonic  index  alike.  The  level  taken  up  by 
the  latter  varies  considerably  in  different  cases,  and 
sufficient  evidence  is  not  yet  forthcoming  to  enable  a 
definite  opinion  to  be  given  as  to  the  import  of  a  steady 
high  or  low  index. 

Taking  into  consideration  the  facts  that  chronicity  is 
always  accompanied  by  a  low  index,  and  that  the  aim  of 
therapeutic  injections  is  to  raise  the  index  to  or  above 
unity,  it  would  appear  rational  to  assume  that  those 
cases  will  do  best  which  settle  down  to  a  steady  index  of 
1  or  over,  while  those  that  settle  down  to  an  index  below 
1  will  go  on  to  chronicity.  Meakin  and  Wheeler  support 
this  view.  They  find  that  the  case  with  an  index  much 
below  1  is  the  case  that  becomes  chronic,  that  recovers  to 
a  certain  extent,  but  can  only  maintain  that  degree 
of  recovery  while  living  under  sanatorium  treatment  ; 
that  the  case,  on  the  other  hand,  which  during  treatment 
shows  a  steady  index  of  1  or  over  is  the  one  which  makes 
a  complete  recovery  if  favourable  conditions  are  main- 
tained for  a  sufficient  time.  They  lay  especial  stress 
on  the  statement  that  it  is  only  to  patients  actually  under- 
going sanatorium  treatment  that  this  opinion  applies. 

Lawson  and  Stewart1  took  the  indices  of  twenty-five 
cases  of  sanatorium  '  cures.'  In  five  of  these  it  was  found 
to  be  between  1-1  and  0-9  ;  in  the  other  twenty  it  was 
0-  8  or  under. 

1  Lancet,  December  9,  1905,  p.  1683. 


90  VACCINE  THERAPY 

In  thirty  other  similar  cases  fourteen  had  indices 
between  0-5  and  0-9,  and  of  these  thirty  cases  twenty- 
nine  had  been  carrying  on  their  usual  occupations,  in 
most  instances  in  towns,  for  periods  ranging  from  six 
months  to  four  and  a  half  years,  and  enjoying  perfect 
health. 

As  to  the  liability  of  cases  with  low  indices  to  relapse, 
nothing  definite  is  at  present  known,  but  authorities  agree 
upon  the  distinct  advisability  of  artificially  raising  to  unity 
or  over  the  indices  in  all  such  cases.  The  cases  which  seem 
to  profit  most  when  tuberculin  injections  are  added  to  the 
other  therapeutic  measures  adopted  at  sanatoria,  appear 
to  be  those  with  initially  low  indices,  although  improve- 
ment is  also  noticeable  in  those  with  indices  above 
unity. 

2.  In  Other  Tubercular  Affections — Lupus. — Bulloch's 
experience  is  that  the  cases  which  do  best  with  Finsen 
light  are  those  with  indices  either  beyond  or  within  the 
normal  limits  ;  those  with  indices  below  0-8  do  worst, 
whereas,  per  contra,  those  cases  which  profit  most  from 
tuberculin  injections  are  those  of  the  latter  class.  Wright 
finds  that  in  those  varieties  of  lupus  where  the  infected 
skin  is  dry  and  scaly,  so-called  lupus  psoriasis,  tuberculin 
is  of  little  avail ;  while  in  suppurating  lupus,  where  mixed 
infection  by  the  Staphylococcus  albus  is  present,  good 
results  can  often  only  be  achieved  by  a  simultaneous 
attack  upon  the  secondary  infection. 

As  regards  other  tubercular  affections,  such  as  those  of 
glands,  peritoneum,  joints,  kidneys,  and  bladder,  no  definite 
rules  can  be  laid  down  beyond  the  general  statement  that  if 
tuberculin  injections  are  not  to  be  given,  the  cases  that 
have  a  steadily  high  index  do  best,  while  those  with  fluctu- 
ating indices  do  badly,  and  those  with  subnormal  indices 


OPSONIC  INDEX  IN  HEALTH  AND  DISEASE     91 

show  little  tendency  to  recover.  These  last  show  the 
relatively  greatest  improvement  under  a  course  of  tuber- 
culin, but  as  experience  increases  it  becomes  more  and 
more  difficult  to  draw  the  line  between  suitable  and  un- 
suitable cases  for  such  treatment,  for  some  cases  which 
have  seemed  the  most  hopeless  have  yet  done  well.  In 
four  cases  of  tubercular  peritonitis  which  relapsed,  White 
found  subnormal  indices  ;  in  one  which  recovered,  an 
index  above  normal. 

3.  In  Other  Infections. — No  general  rule  whatever 
can  here  be  laid  down.  A  low  index  denotes  lack 
of  immunizing  response,  and  therefore  chronicity  or 
complete  ultimate  failure  of  the  protective  mechanism ; 
a  high  index  obviously  denotes  an  attempt  at  adequate 
immunizing  response.  The  attempt  may  succeed,  or  it 
may  fail,  either  because  it  is  inadequate  or  because  the 
other  protective  mechanism  breaks  down.  That  death  is 
often  preceded  by  an  abnormally  high  index  has  mystified 
many  ;  in  reality  there  is  no  difficulty  in  understand- 
ing it  at  all.  It  is  then  a  last  supreme  effort  on  the 
part  of  the  body  to  overcome  the  infection ;  into  what 
may  be  its  most  powerful  line  of  defence  it  hurls  up  all 
its  reserve  supports,  but  in  vain.  The  other  protective 
mechanisms  do  not  suffice  ;  the  vanguard  is  strong  enough, 
but  the  flanks  are  weak  and  the  rear  unguarded.  For 
instance,  in  a  case  of  septicaemia  the  opsonin  may  be 
adequate — perhaps  more  than  adequate — but  what  avail 
is  this  if  the  myocardium  has  been  hopelessly  weakened  by 
toxin  ?  Of  what  use,  again,  is  an  index  of  15  in  cerebro- 
spinal  meningitis,  when  the  cerebro-spinal  fluid  has  an 
index  of  zero  and  all  the  cerebral  centres  are  overloaded 
with  toxin  ?  Yet  the  body  will  keep  up  the  fight  to  the 
bitter  end,  and  in  a  last  effort  perhaps  raise  the  index  to  30. 


92  VACCINE  THERAPY 

THE  VALUE  OF  THE  OPSONIC  INDEX  AS  A  GUIDE  IN 
THERAPEUTICAL  IMMUNIZATION. 

It  is  with  considerable  diffidence  that  I  enter  upon  the 
task  of  discussing  this  very  vexed  and  much-debated 
subject ;  the  doubts  cast  by  insufficiently  skilled  ob- 
servers and  others  upon  the  accuracy  of  the  present 
methods  of  determining  the  opsonic  index,  and  upon  its 
value  as  a  measure  of  the  immunizing  response  of  the 
human  organism  to  inoculation,  have  sunk  so  deeply  that 
there  are  those  who  say,  '  Away  with  the  opsonic  index  ; 
let  us  immunize  without  it  !'  There  are  those,  again,  who 
hold  views  diametrically  opposed  to  these,  and,  proceeding 
with  the  utmost  caution,  would  never  give  an  inoculation 
without  prior  determination  of  the  index  ;  and  there  are 
those,  again,  who  reserve  this  observation  for  such 
occasions  as  when  they  find  themselves  in  difficulties. 
My  own  procedure  with  patients  is  as  follows  :  No  matter 
what  the  infection  may  be — a  simple  staphyloma,  a  case  of 
pulmonary  phthisis,  or  a  systemic  infection — I  always 
explain  that  in  the  present  state  of  knowledge  I  feel  that 
the  best  results  are  only  to  be  secured  by  systematic 
observation  of  the  opsonic  index.  Should  financial  con- 
siderations intervene,  then  two  alternatives  are  offered  : 
the  occasional  determination  of  the  index  at  such  times 
as  clinical  symptoms  point  to  alternation  of  dosage,  or  of 
frequency  of  administration,  or  the  conduct  of  the  case 
with  the  aid  of  past  experience  and  clinical  observation. 
In  both  these  cases  I  cast  all  responsibility  for  possible 
failure  upon  the  patient  ;  in  other  words,  I  do  not  think 
that  inability  on  their  part  to  pay  for  a  series  of  difficult 
laboratory  estimations  should  deprive  them  of  the 
benefits  likely  to  accrue  from  a  course  of  inoculations, 


OPSONIC  INDEX  IN  HEALTH  AND  DISEASE     93 

but  they  cannot  expect  the  most  favourable  or  speedy 
issue. 

The  difficulties  liable  to  be  encountered  by  those 
who  would  undertake  the  conduct  of  therapeutical  im- 
munization without  the  guidance  of  the  opsonic  index 
are  so  especially  clearly  outlined  by  Sir  A.  E.  Wright, 
in  his  illuminating  article  in  the  Practitioner  for  May, 
1908,  that  I  cannot  do  better  than  make  the  following 
extract  : 

'  The  suggestion  has  been  proffered  by  many  that  the 
clinical  symptoms  of  the  patient  will  furnish  the  immu- 
nizator  with  a  guide  by  which  he  may  regulate  his  pro- 
cedure, but  to  this  suggestion  many  objections  may  be 
taken.  For  instance — 

'  1.  Even  in  the  case  of  localized  infections,  where 
objective  and  other  signs  are  freely  presented,  many 
difficulties  of  interpretation  may  be  present.  Thus,  in 
lupus  secondarily  infected  by  streptococci  incidental 
exacerbations  of  the  secondary  infection  may  completely 
mask  amelioration  in  the  tubercular  infection  ;  and  this 
is  equally  true  of  other  mixed  infections.  Again,  varia- 
tions in  the  size  of  tubercular  glands,  and  perhaps  changes 
in  the  amount  of  effusion  into  tubercular  joints,  may 
occur,  independently  of  any  progress  or  regress  of  the 
infection,  directly  as  the  result  of  changes  in  the  coagula- 
bility or  viscidity  of  the  blood. 

'2.  The  clinical  symptoms,  even  when  conveying  accu- 
rate information  with  respect  to  the  conditions  obtaining 
in  the  focus  of  infection,  may  suggest  quite  a  wrong 
picture  of  the  conditions  obtaining  in  the  circulating 
blood. 

'  3.  The  fact  that  the  patient's  general  condition  remains 
undisturbed  does  not  warrant  us  in  assuming  that  the 


94 

antibacterial  potency  of  the  blood  is  not  undergoing 
momentous  fluctuations  under  the  influence  of  sponta- 
neous auto-inoculations  such  as  the  immunizator  should 
take  into  account  in  regulating  his  dosage  and  in  inter- 
spacing his  inoculations. 

'  4.  Many  conditions  there  are  of  a  strictly  localized 
infection,  where  the  conditions  are  unfavourable  to  the 
observation  of  changes  in  the  condition  of  the  focus 
of  infection,  such  as  the  majority  of  cases  of  tuber- 
cular adenitis,  arthritis,  lupus,  and  phthisis.  Of 
course  the  clinical  symptoms  would  ultimately  inform 
as  to  the  results  of  the  course  of  vaccine  therapy,  but 
this  information  arrives  too  tardily  to  be  of  service. 
The  necessity  is  obvious  of  determining,  from  time  to 
time,  what  the  scheme  of  dosage  is  achieving  for  good 
or  ill. 

'  5.  In  acute  febrile  conditions,  while  it  is  true  that  the 
rule  is  to  find  an  inverse  relation  of  temperature  to 
antibacterial  potency,  it  is  certainly  not  the  invariable 
rule.  It  is  notorious  that  excessive  intoxication  may 
condition  a  fall  in  temperature,  and  it  is  conceivable  that 
a  rise  in  temperature  may  sometimes  be  associated  with 
efficient  immunizing  response. 

'  6.  Finally,  there  are  cases  where  all  local  and  general 
symptoms  are  in  abeyance,  or  have  returned  to  the 
condition  which  prevailed  previous  to  inoculation.  Here 
we  are  face  to  face  with  the  difficulty  as  to  whether  the 
patient  is  now  immune,  whether  the  infection  has  been 
eradicated  or  still  persists.' 

With  these  important  considerations  before  us,  I  think 
that  even  the  most  prejudiced  will  admit  that  thera- 
peutic immunization  is  a  course  not  lightly  to  be  em- 
barked upon,  and  that  in  the  present  state  of  our 


OPSONIC  INDEX  IN  HEALTH  AND  DISEASE     95 

knowledge  the  greatest  caution  is  to  be  used  if  the  pilotage 
of  the  opsonic  index  be  dispensed  with,  especially  in  cases 
where  the  effects  of  a  mistake  will  be  of  serious  import  to 
the  patient.  This  question  will,  incidentally,  be  further 
referred  to  in  the  chapters  dealing  with  the  specific 
infections. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS 

I.  ETIOLOGY  OF  TUBERCULOSIS. 

IT  is  a  most  unfortunate  thing  that  in  all  that  appertains 
to  the  tubercle  bacillus  there  is  still  so  much  that  is  un- 
certain. Out  of  the  chaos  a  gleam  of  light  appears,  but 
a  vast  amount  of  work  remains  yet  to  be  done  before  the 
immunizator  can  approach  a  case  of  tuberculosis  with 
any  great  degree  of  confidence. 

Even  upon  the  question  of  aetiology  finality  has  not 
yet  been  reached.  Koch  and  Cornet  still  uphold  that 
the  disease  is  spread  by  direct  infection  from  individual 
to  individual,  and  that  the  human  and  bovine  types  of 
bacilli  are  quite  distinct.  A  severe  blow  has  been  dealt 
to  this  theory  by  the  experiments  of  Vansteenberghe  and 
of  Whitla  and  Symmers,  which  bear  out  Behring's  view 
that  direct  infection  is  not  proven,  and  that  nearly  all 
tuberculosis  is  the  result  of  infection  by  means  of  con- 
taminated milk.  Vansteenberghe  and  Grysez,  by  means 
of  most  careful  feeding  experiments  upon  animals 
through  an  cesophageal  tube  with  tubercle  bacilli,  showed 
that  the  organisms  were  absorbed  by  the  intact  intestinal 
mucosa,  and  produced  extensive  tuberculous  deposits  in 
the  mesenteric  and  other  glands,  lungs  and  other  viscera  ; 
within  even  ten  days  the  whole  lymphatic  system  became 
infected,  and  in  fifty  to  sixty  days  the  cervical  glands 

96 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS     97 

were  deeply  infected.  Whitla  and  Symmers  fed  animals 
through  a  tube  with  china  ink  and  carbon  particles,  and 
also  injected  them  both  intravenously  and  intraperi- 
toneally  with  the  same  preparations.  In  each  instance 
they  were  able  to  demonstrate  that  the  solid  particles 
were  very  rapidly  carried  to  the  lung.  Vansteenberghe 
has  pointed  out  a  very  remarkable  difference  between 
young  and  old  animals  in  the  permeability  of  the  lym- 
phatic glands.  In  the  case  of  the  former  the  bacteria 
are  rapidly  filtered  off  by  the  glandular  tissue,  which 
accordingly  becomes  deeply  infiltrated,  while  the  lungs 
may  remain  free  ;  whereas  in  old  animals  the  glands  have 
not  this  power,  and  great  numbers  of  the  bacteria  pass 
through  them,  and  reach  the  lung  via  thoracic  duct  and 
blood-stream.  Flugge,  Ribbert,  and  Schrotter  hold  that 
the  droplets  of  sputum  laden  with  tubercle  bacilli  coughed 
up  by  an  infected  individual  are  an  important  source  of 
infection  ;  and  Flugge  adduces  experiments  to  show  that 
pulmonary  phthisis  can  be  induced  in  a  number  of 
animals  by  inhalation,  and  that  the  number  of  bacilli 
required  to  produce  infection  by  ingestion  is  millions  of 
times  greater  than  that  required  to  produce  infection 
by  inhalation,  and  consideration  of  cases  of  primary 
laryngeal  tuberculosis  leads  to  the  conclusion  that  such 
cases  can  only  have  been  induced  by  inhalation. 

Pottenger  says  :  '  The  presumption  is  quite  strong  that 
phthisis  is  primarily  a  glandular  disease,  the  bacilli 
gaining  entrance  through  the  mucous  membrane,  and 
being  either  destroyed  or  deposited  in  the  lymphatic 
glands.  Infection  may  take  place  in  childhood,  but  death 
may  not  occur  till  adolescence  or  even  old  age.  The 
bacilli  may  remain  in  the  lung  during  an  entire  lifetime 
and  produce  no  recognizable  symptoms  ;  they  may  re- 

7   * 


98  VACCINE  THERAPY 

main  and  produce  symptoms  at  times,  and  yet  never 
cause  advanced  tuberculosis,  or,  being  there,  they  may 
cause  an  active  disease  at  any  time.'  He  points  out  that 
the  floors  of  rooms  occupied  by  phthisis  patients  are  very 
apt  to  be  contaminated,  and  the  grave  consequent  risk 
to  a  child  crawling  about  on  the  floor  of  constantly  putting 
his  infected  hands  into  his  mouth.  Ravenel  has  pointed 
out  that  the  chances  of  infection  via  the  tonsil  either 
from  inhaled  bacilli  of  human  origin  or  from  the  bovine 
bacilli  in  infected  milk  also  have  to  be  considered, 
especially  in  view  of  Grober's  demonstration  of  a  direct 
route  to  the  pleura  and  lungs  via  the  cervical  lymph  - 
glands. 

That  tubercle  bacilli  can  pass  through  the  intact  mucous 
membrane  of  the  intestinal  tract  must  now  be  regarded 
as  proven,  and  MacConkey  and  MacFadyen  have  found 
virulent  tubercle  bacilli  present,  usually  in  the  mesenteric 
glands,  of  about  25  per  cent,  of  children  who  have  died 
from  non-tuberculous  causes.  Against  this  theory  that 
the  common  route  of  infection  is  via  the  intestine  is  to 
be  set  the  fact  that,  in  Siam  and  Japan,  where  all  children 
are  breast-fed,  and  cow's  milk  is  not  drunk,  pulmonary 
phthisis  is  yet  rampant.  A  similar  state  of  affairs  is 
found  in  Egypt,  Malaya,  India,  and  Persia. 

By  the  upholders  of  this  theory  of  intestinal  infection 
by  means  of  cow's  milk  a  very  difficult  question  remains 
to  be  answered.  The  minute  and  careful  examinations 
of  Spengler  in  Germany  and  of  Pottenger  in  America, 
and  confirmed  by  numerous  other  observers,  establishes 
it  as  a  fact  that  by  far  the  greater  proportion  of  lung  cases 
are  infected  by  the  human  type  of  bacillus.  How,  then, 
can  these  cases  have  been  set  up  by  an  infection  of 
bovine  origin,  unless  it  be  that  the  latter  type  becomes 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS     99 

converted  into  the  former  by  long  residence  in  the  human 
body  ? 

I  would  suggest  that  all  extremists  are  in  error,  and 
that  there  are  numerous  modes  of  entrance  of  the  bacilli 
into  the  body  ;  that  they  may  gain  access  in  contamin- 
ated milk  and  butter  through  the  intact  mucous  membrane 
of  the  intestinal  tract,  lodge  in  the  mesenteric  and 
bronchial  glands,  and  perhaps  find  their  way  into  the 
lung  tissue  through  the  blood  -  stream ;  that,  again, 
human  bacilli  may  similarly  be  swallowed  in  dust  and 
sputum  and  follow  the  same  course  ;  that  either  bovine 
in  milk  or  human  in  sputum  may  be  caught  up  by  the 
tonsil  and  lodge  in  the  cervical  glands  ;  or  yet,  again,  that 
inhalation  may  be  responsible  for  infection  via  the 
respiratory  tract.  This  question  of  aetiology  only  affects 
the  immunizator  in  so  far  as  it  sheds  light  upon  the 
variety  of  the  bacillus  at  work  in  any  given  case. 

II.  METHODS  OP  DIAGNOSIS  OF  TUBERCULOUS 
INFECTION. 

(.4)  By  Clinical  Signs. — These  will  be  found  fully  de- 
scribed in  any  such  work  as  Pottenger's  '  Pulmonary 
Tuberculosis.' 

(B)  Special  Methods  not  Dependent  upon  Determination 
of  the  Index. 

1.  The  Old  Tuberculin  Test. — If  a  healthy  individual 
receive  an  injection  even  so  large  as  0-01  c.c.  of  old  tuber- 
culin (Koch),  no  symptoms  beyond  slight  local  tenderness 
will  be  exhibited.  The  case  is  very  different  with  a 
person  afflicted  with  tuberculosis,  especially  if  in  an 
early  stage.  If  the  dose  of  tuberculin  be  extremely  small, 
no  effect  may  be  noted  ;  if  a  larger,  a  local  hypersemia 

7—2 


100  VACCINE  THERAPY 

of  the  infected  area  ;  if  still  larger,  a  congestion  ;  while 
if  larger  still,  a  constitutional  disturbance  of  varying 
degrees  of  severity  will  result.  If  the  infected  areas  be 
visible,  as  in  the  larynx  or  pharynx,  the  hyperaemia  and 
congestion  can  be  readily  detected.  In  the  lung  there  is 
an  increase  in  the  symptoms  confined  to  the  area  of  infec- 
tion ;  the  auscultatory  signs  are  magnified,  and  resemble 
a  catarrhal  condition  of  greater  degree.  Fine  rales  may 
appear  where  none  were  to  be  found  previously,  or  their 
number  may  increase.  Careful  charting  of  the  signs 
before  and  during  the  reaction  are  therefore  necessary. 

It  is  possible  to  have  this  local  reaction  without  any 
general  one.  If  the  latter  be  present,  a  few  hours  after 
the  administration  of  a  small  dose  of  tuberculin  the 
patient  begins  to  feel  a  little  nervous  or  tired,  and  per- 
haps has  a  heavy  feeling  about  the  limbs.  With  this 
there  may  be  a  slight  rise  of  temperature  of  a  fraction  of 
a  degree  or  a  slightly  accelerated  pulse.  With  a  larger 
dose  the  tired  feeling  and  heaviness  of  the  limbs  becomes 
a  true  ache,  which  extends  to  the  back  and  head,  and  the 
feeling  is  that  of  an  oncoming  cold.  With  this  the 
temperature  usually  rises  one  or  two  degrees,  and  the 
patient  may  develop  a  cough  where  none  was  present 
before.  If  the  dose  be  still  larger,  the  patient  may  have 
a  rigor,  and  nausea  and  vomiting  occur. 

The  more  experienced  the  physician,  the  less  the 
amount  of  general  reaction  that  he  requires  to  establish 
a  diagnosis,  and  an  endeavour  is  made  so  to  adjust  the 
dose  that  a  rise,  at  all  events,  of  not  more  than  1°  F.  shall 
occur  in  the  temperature.  If  this  be  already  above 
100°  F.,  the  use  of  the  test  is  contra-indicated — at  all 
events,  until  rest  and  other  appropriate  means  have  re- 
duced the  temperature  to  the  region  of  the  normal. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    101 

Inasmuch  as  the  reaction  usually  shows  itself  in  from 
eight  to  twenty  hours,  the  dose  of  tuberculin  is  best 
given  at  eight  or  nine  o'clock  at  night,  the  temperature 
being  then  taken  at  six  o'clock  next  morning  and  at  two- 
hourly  intervals.  Examination  of  the  chest  for  the 
local  reaction  should  begin  at  the  same  time,  and  be 
repeated  at  three  to  four  hourly  intervals  until  the 
presence  or  absence  of  local  reaction  is  established.  For 
the  purpose  of  the  test  Koch's  old  tuberculin  is  usually 
employed.  Some  people  being  very  sensitive  to  it,  it 
is  best  to  begin  with  a  dose  of  only  0-0001  c.c.,  to  which 
only  very  exceptionally  is  any  response  made.  Should 
no  reaction  occur,  the  dose  is  increased  ;  0-001,  0-003, 
0-005,  0-007,  0-01  c.c.  being  used  in  succession  at  one  or 
two  daily  intervals  until  a  positive  result  is  secured,  as  is 
usually  the  case  with  the  second  or  third  of  these  doses  in 
tuberculous  cases.  A  negative  result  with  the  last  of 
these  doses  is  considered  to  be  final.  It  must  be  re- 
membered that  some  cases  of  advanced  phthisis  will  not 
respond  to  the  test,  while  it  is  also  possible  that  cases 
infected  by  the  bovine  bacillus  may  not  react  to  tuber- 
culin of  human  origin  (as  in  eleven  cases  of  Peel  Ritchie, 
referred  to  on  p.  88).  It  has  also  been  stated  that 
certain  cases  of  syphilis  have  given  a  positive  reaction, 
but  against  this  it  must  be  borne  in  mind  that  sufficient 
proof  that  these  cases  were  not  also  infected  somewhere 
by  the  tubercle  bacillus  has  not  been  always  forthcoming. 

Contra-indications  to  use  of  the  test  are  :  ( 1 )  If  tempera- 
ture rises  above  98-  6°  in  the  axilla,  or  99°  F.  in  the  mouth  ; 
(2)  if  definite  signs  of  tuberculosis  be  present,  if  tubercle 
bacilli  be  present  in  the  sputum,  or  if  there  has  been  a 
recent  attack  of  haemoptysis  ;  (3)  if  there  be  grave  renal 
or  cardiac  trouble ;  (4)  if  patient  be  subject  to  epileptic  fits. 


102  VACCINE  THERAPY 

2.  Von   Pirquefs   Cutaneous   Reaction.1 — Von    Pirquet 
employed  a  solution  consisting  of  Koch's  old  tuberculin 
1  part,  5  per  cent,  carbolic  acid  1  part,  normal  salt  solu- 
tion 2  parts,  and  showed  that  by  its  means  a  reaction 
could  be  obtained  in  persons  infected  by  the  tubercle 
bacillus,   which  is   but  rarely  obtainable  with   healthy 
individuals.     The  skin  of  the  upper  arm  is  cleansed  with 
ether.     Two  drops  of  the  above  solution  are  then  placed 
on  the  skin  about  2  inches  apart,  and  the  skin  slightly 
abraded  by  the  aid  of  a  lancet,  which  is  then  disinfected, 
and  a  third  abrasion  made  between  the  other  two  to  serve 
as  a  control. 

After  forty-eight  hours  some  redness  and  oedema 
result,  and  a  papule  resembling  that  of  vaccinia  soon 
appears  at  the  two  infected  areas,  but  not  at  the  control 
one.  Within  a  week  the  pustule  dries  up,  and  the  re- 
action subsides. 

The  advantage  of  this  test  is  that,  as  there  is  no  tem- 
perature reaction,  it  can  be  employed  in  pyrexial  cases 
and  in  children  without  fear  of  constitutional  disturbance. 
It  has  been  found  especially  trustworthy  in  the  first  three 
years  of  life  ;  it  is  not  quite  so  reliable  after  that  up  to 
ten  or  twelve,  and  still  less  so  afterwards,  especially  in  the 
very  cachectic. 

3.  The    Ophihalmo-Reaction    of    Calmette    and     Wolff 
Eisner. — These    two    investigators    simultaneously    dis- 
covered that  a  diagnosis  of  tuberculosis  can  be  estab- 
lished in  a  very  large  percentage  of  cases  in  the  following 
way  : 

By  means  of  95  per  cent,  alcohol  a  precipitate  is  ob- 
tained   from    Koch's    old    tuberculin.     This    is    washed 
and  dried,  and  made  up  in  a  solution  of  normal  salt 
1  Deut.  Med.  Woch.,  May  28  and  30,  1907. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    103 

solution  to  a  strength  of  0-5  per  cent.  One  or  two  drops 
of  this  solution  are  introduced  into  the  eye  of  the  person 
supposed  to  be  tuberculous  near  the  inner  canthus,  and 
the  eye  kept  open  for  a  few  seconds.  A  positive  reaction 
appears  in  from  eight  to  twenty-four  hours,  and  begins 
with  lachrymation,  going  on  to  reddening  of  the  con- 
junctiva, and  in  severe  cases  to  fibrinous  exudation.  The 
amount  of  reaction  is  no  evidence  of  the  severity  of  the 
disease,  and  varies  from  slight  injection  of  the  caruncle — 
which  can  only  be  detected  by  comparison  with  the  un- 
treated eye — to  all  the  signs  of  a  severe  purulent  con- 
junctivitis with  oedema  of  the  lids.  The  reaction  usually 
passes  off  in  three  to  four  days,  but  may  last  for  a  week,  or 
even  longer.  As  a  rule,  little  discomfort  is  caused,  but 
occasionally  there  may  be  sufficient  pain  to  require 
treatment.  In  cases  free  from  tuberculous  infection  no 
reaction  soever  is  obtained. 

From  a  summary  of  all  the  published  observations,  it 
would  appear  that  95  per  cent,  of  all  cases  suffering  from 
active  tuberculous  infection  give  a  positive  reaction. 
Moribund  cases  and  a  few  of  miliary  tuberculosis  refuse 
to  respond,  while  in  cases  supposed  to  be  quiescent  either 
a  positive  or  a  negative  result  may  be  obtained. 

Any  affection  soever  of  the  eye  already  present  is  an 
absolute-contra-indication  to  the  employment  of  this  test. 
Several  accidents,  such  as  corneal  ulceration  and  iritis, 
have  been  reported  to  have  resulted  from  its  use,  and 
have  led  to  the  employment  of  a  solution  of  1  in  200 
instead  of  one  of  double  this  strength,  as  was  first  advo- 
cated. It  is,  perhaps,  advisable  to  use  a  still  weaker 
solution — say  1  in  500 — in  the  first  place,  and  only  if 
this  prove  negative,  one  of  a  strength  of  1  in  200  two  or 
three  days  later.  The  accidents  which  undoubtedly  did 


104  VACCINE  THERAPY 

occasionally  follow  the  use  of  the  1  per  cent,  solution  have 
tended  to  bring  this  test  into  a  certain  amount  of  dis- 
credit, but  in  careful  hands  these  may  well  be  obviated 
in  the  future  ;  and  this  most  valuable  method  of  diagnosis 
in  doubtful  cases  occupies  a  deservedly  assured  position. 

(4)  The  method  of  observing  deviation  of  complement 
(Gengou-Bordet  effect)  must  be  mentioned,  but  the  diffi- 
culties of  carrying  out  the  test  are  too  great  to  enable  it 
to  be  employed  in  practical  diagnosis. 

(C)  Special  Method  Dsependent  upon  Observations  of  the 
Opsonic  Index. — These  have  all  been  referred  to  pre- 
viously, but  are  here  recapitulated  that  attention  may  be 
drawn  to  a  few  important  points. 

1.  Simple    determination    of    the    index,    repeated    if 
necessary. 

2.  Determination  of  the  index  before,  and  at  various 
intervals  after,  the  production  of  an  auto-inoculation  by 
movement,  massage,  Bier's  congestion,  etc. 

3.  In  women  comparative  determinations  before  and 
during  a  menstrual  period. 

4.  Determination  of    the  index  before  injection  of  a 
small   dose,   say  0-00002   c.c.   T.R.,  and    one   day,   two 
days,  and  ten  days  after,  with  a  view  to  the  observation 
of  the  extent   and   duration   of   the   resulting   negative 
phase,  which  in  healthy  people  will  be  very  slight  and 
of  short  duration — viz.,  amount  to  0-1  or  0-2  and  last 
one  or  two  days — in  the  infected  it  will  be  greater  and 
of  longer  duration— viz.,  0-3  or  0-4— and  may  last  even 
a  week  or  a  fortnight,  or  longer  (vide  p.  22). 

It  must  be  noted  that  if  the  patient  be  infected  by 
bacilli  of  the  bovine  type,  no  response  may  be  elicited 
by  injection  with  T.R.  of  human  origin,  but  will  be  by 
T.R.  of  bovine  origin.  It  is,  therefore,  perhaps  best  in 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    105 

performing  the  test  to  use  both  T.R.'s  and  estimate  the 
indices  to  both  varieties  of  the  bacillus.  This  failure  to 
respond  to  T.R.  of  human  origin  was  noted  by  Stewart 
and  Ritchie  in  about  10  per  cent,  of  their  cases,1  and  in 
eleven  cases  of  Ritchie,  referred  to  on  p.  88. 

5.  The  absorption  method  of  Peel  Ritchie  (vide  p.  87), 
with  diluted  and  undiluted,  heated  and  unheated,  sera. 

The  sera  of  two  of  the  eleven  cases  there  referred  to 
which  failed  to  give  the  absorption  reaction  with  tubercle 
bacilli  of  human  origin  were  tested  with  bacilli  of  bovine 
origin,  and  gave  the  characteristic  reaction. 

III.  TYPES  OF  THE  TUBERCLE  BACILLUS  :  HUMAN  AND 

BOVINE. 

Assuming  now  that  a  definite  diagnosis  of  tuberculosis 
has  been  made,  before  beginning  a  course  of  tuberculin 
inoculations  it  is  obviously  advisable  that  the  variety  of 
the  organism  at  work,  whether  of  the  human  or  bovine, 
or  of  both  types  together,  should  be  determined. 

Until  quite  recently  the  very  important  bearing  of 
this  upon  the  choice  of  the  appropriate  variety  of  tuber- 
culin to  be  employed  in  any  given  case  received  no 
consideration.  Tuberculin  of  human  origin  was  alone 
employed,  and  was  given  indiscriminately.  To  this 
cause  must  be  imputed  many  of  the  past  failures  of 
tuberculin,  and  the  due  recognition  of  this  most  im- 
portant point  cannot  fail  to  result  in  the  near  future 
in  a  great  advance  in  tuberculin  therapy. 

Tuberculous  cases  may  for  this  purpose  be  divided 
into  two  categories  :  (1)  Those  in  which  the  bacilli  can 
be  obtained  for  examination  and  culture,  whether  from 
the  sputum,  urine,  faeces,  or  purulent  exudates  (special 
1  Edinburgh  Medical  Journal,  May,  1907. 


106  VACCINE  THERAPY 

methods  for  the  examination  and  isolation  of  the  bacilli 
applicable  to  different  cases  will  be  found  in  the  Appen- 
dix) ;  (2)  those  cases  in  which  specimens  of  the  bacilli 
cannot  be  obtained  for  examination,  and  indirect  means 
of  arriving  at  a  correct  diagnosis  must  be  employed. 

It  now  becomes  necessary  to  consider  whether  it  is 
possible  accurately  to  differentiate  the  human  from  the 
bovine  variety  of  the  tubercle  bacillus.  Of  the  possi- 
bility of  human  tuberculosis  being  due  to  the  bovine 
bacillus  there  is  now  no  doubt.  Upon  that  point  the 
German  and  English  Government  Commissions  and 
numerous  independent  observers  are  in  complete  agree- 
ment. Upon  the  possibility  of  always  being  able  to  say 
to  which  type  a  given  bacillus  belongs  there  is  not  the 
same  unanimity  of  opinion. 

Eastwood1  says  that  '  the  evidence  of  capacity  for 
modification  of  the  tubercle  bacillus  is  sufficient  to  make 
caution  necessary  before  it  is  concluded  that  a  case  of 
human  tuberculosis  has  not  originated  in  bovine  infection, 
because  the  associated  bacilli  are  of  the  Eugenic  variety 
(i.e.,  human  type).  In  course  of  long  residence  in  the 
human  body,  a  bacillus,  originally  of  bovine  origin, 
might  experience  a  modification  of  some  of  those  charac- 
teristics which  are  met  with  in  bacilli  freshly  isolated 
from  the  bovine,  and  owing  to  this  modification  might 
be  indistinguishable  from  bacilli  derived  from  previous 
cases  of  human  disease.  The  differences  in  virulence  of 
different  bacilli,  in  the  types  of  histological  lesion  pro- 
duced by  identical  bacilli,  and  in  the  cultural  characters 
of  different  bacilli  all  overlap  and  interweave  so  closely 
that  it  is  impossible  to  find  [a  somewhat  bold  statement] 

1  Second  Report  of  Royal  Commission  on  Tuberculosis,  vol.  ii.  of 
Appendices  thereto. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    107 

an  adequate  scientific  basis  for  separating  these  bacilli 
into  two  or  more  families.'  To  this  it  may  be  replied 
that  within  the  past  two  years  the  entity  of  typhoid  fever 
has  been  entirely  upset ;  that  no  longer  is  the  Bacillus 
coli  communis  boldly  differentiated  from  the  Bacillus 
typhosus  ;  that  not  only  are  paracolon  bacilli  recognized, 
but  also  several  varieties  of  paratyphoid  ;  and  that  no 
pathologist,  despite  the  variation  in  pathogenicity 
exhibited,  not  only  by  the  different  groups,  but  even 
by  different  members  of  the  same  groups,  considers  it  im- 
possible to  find  an  adequate  scientific  basis  for  separating 
these  bacilli  into  two  or  more  families. 

The  cultural  characteristics  of  typical  members  of  the 
two  groups  are  set  out  in  the  following  table  : 


Human  or  Eugenic  Type. 


Bovine  or  Dysgonic  Type, 


1.  In  broth  rapid  formation 
of  thick,  tough,  wrinkled  pel- 
licle, which  shows  no  ten- 
dency to  sink.  If  the  broth 
be  slightly  acidulated  to  begin 
with,  this  reaction  never  en- 
tirely disappears. 


2.  On     glycerine      agar     it 
usually  forms  a  dense,  warty, 
wrinkled  layer. 

3.  On  potato  there  is  rapid 
formation     of     a    heaped- up 
richly  pigmented  growth. 


1.  In    broth    pellicle    often 
slow   in   making   its   appear- 
ance ;  generally  very  delicate, 
semi- translucent  and  speckled 
with   a    variable   number   of 
white   spots ;    occasionally  it 
is  opaque.     It  is  very  thin  on 
the  whole,  and,  with  the  ex- 
ception  of  a   few  irregularly 
thickened  areas,  uniform.  The 
acidity  of  the  broth  may  be 
entirely  neutralized  and  its  re- 
action even  become  alkaline. 

2.  On  glycerine  agar  a  thin 
grey  haze   on  the  surface  is 
generally  all  that  is  to  be  seen 
at  the  end  of  five  or  six  weeks. 

3.  On  potato  at  the  end  of 
five  or  six  weeks  the  growth 
does  not  consist  of  more  than 
a  few  grey  colonies  or  streaks. 


108  VACCINE  THERAPY 

In  addition  to  these  cultural  differences,  Spengler,1  whose 
experience  of  tubercle  bacilli  is  probably  unique,  considers 
that  the  two  varieties  present  these  further  differences  : 

1.  In  Morphology  and  Methods  of  Staining  (for  which 
see    Appendix). — When    suitably    stained     the    bovine 
bacillus  is  the  much  larger  and  thicker.     The  bovine  has 
a  thicker  and  sharper  envelope  than  the  human,  but  when 
stained  by  the  ordinary  method  this  envelope  is  injured 
by  the  acid  and  heat,  being  composed  of  a  wax  of  low 
melting-point. 

2.  In    Sporulation. — The    bovine    bacilli,    by    special 
methods  of  staining,  may  be  seen  to  contain  spores  within 
them,  while  human  do  not  (vide  Appendix). 

3.  In  Agglutination. — In  pure  culture  they  agglutinate 
differently.     What  will  agglutinate  the  one  will  not  the 
other,  showing  that  they  produce  different  antibodies. 
The  serum  of  the  human  being  when  affected  by  tuber- 
culosis usually  agglutinates  both,  speaking  for  the  double 
etiology  (vide  infra). 

4.  In  the  Toxins. — A  patient  infected  principally  with 
bovine  bacilli  is  most  sensitive  to  the  toxins  of  the  bovine 
bacillus,    and    one   infected   principally   with   human   is 
most  sensitive  to  toxins  from  the  human. 

5.  In    their    Localization    in    the    Body. — The    human 
bacillus  demands  more  oxygen  than  the  bovine,  hence  is 
found  nearer  to  the  atmosphere  in  the  tissues.    They  infect 
the  lungs  principally  ;  while  tuberculosis  of  the  intestines, 
kidneys,  bladder,  and  glands  is  more  apt  to  be  by  the 
bovine  bacillus.     When  the  larynx  is  infected,  the  deep 
ulcerations  are  most  apt  to  be  due  to  bovine,  the  more 
superficial  to  the  human  bacillus. 

1  Wien.  Med.  Woch.,  1902,  No.  14 ;  Zeitschrift  f.  Hijg.  u.  Infect., 
Bd.  xlix.,  1905,  etc. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    109 

It  is  perfectly  obvious  that  very  special  training  is 
necessary  before  even  an  attempt  can  be  made  to  differ- 
entiate between  the  human  and  bovine  bacillus ;  and 
even  granting  the  skill,  the  time  necessary  for  such  an 
examination  will,  as  a  rule,  be  lacking.  Where  the 
bacilli  can  be  obtained  and  isolated  (for  methods  see 
Appendix),  I  would  maintain  that  all  experience  of 
vaccine  therapy  derived  from  the  study  of  other  varieties 
of  bacteria  would  indicate  that  an  autogenous  vaccine, 
prepared  from  cultures  of  the  patient's  own  bacilli,  will 
certainly  be  the  one  most  appropriate  for  him.  This  has 
now  been  done  in  a  number  of  cases,  but  no  statistics  are 
yet  available  as  to  the  relative  advantages  of  such  a 
vaccine. 

Should  no  secretion  be  available  in  which  the  bacilli 
may  be  examined,  it  is  obvious  that  methods  other  than 
the  above  must  be  adopted  in  order  to  ascertain  the 
variety  of  the  infecting  organism.  Several  methods  are 
here  available  : 

1.  See  method  C  (4),  p.  104. 

2.  See  method  C  (5),  p.  105. 

3.  Advantage  may  be  taken  of  Spengler's  observation 
that  a  patient  infected  solely  or  principally  with  bovine 
bacilli  is  most  sensitive  to  the  toxins  of  the  bovine  bacillus, 
and  one  infected  solely  or  principally  with  human  is  most 
sensitive    to    the    toxins    of    the    human    bacillus.     The 
patient  is  put  to  bed  till  the  temperature  chart  no  longer 
shows    violent    fluctuations,    and    tuberculin    of   human 
origin    given    diagnostically   (see   p.    99)   till    a   definite 
temperature  reaction  is  obtained,  or,  failing  that,  till  the 
maximum  dose  has  been  given.     In  the  former  event 
the  administration  of  the  same  or  a  slightly  larger  dose 
of  tuberculin   of  bovine   origin  should   almost   at   once 


110  VACCINE  THERAPY 

re-establish  the  temperature  either  to  or  below  its  former 
level ;  in  the  latter  case  it  should  result  in  a  rise  of  tem- 
perature, which  will  be  correspondingly  depressed  by 
another  similar  dose  of  tuberculin  of  human  origin. 
Care  and  close  observation  are,  above  all,  necessary  for 
the  success  of  this  method. 

Considerable  help  may  be  anticipated  from  a  careful 
study  of  the  several  effects  of  therapeutic  doses  of  the 
two  tuberculins  upon  the  opsonic  index  in  a  given  case, 
but  the  necessary  data  have  not  as  yet  been  worked  out. 


Statistical  Results  of  Observations  carried   out    according 
to  the  Above  Methods. 

1.  The  German  Government  Commission  examined 
fifty-six  cases  of  human  tuberculosis,  with  the  following 
results  :  In  fifty  cases  they  found  the  human  type,  in  the 
remaining  six  the  bovine  type.  These  latter  were  all  in 
children  under  seven  years  of  age,  and  were  affected  as 
follows  : 

(1)  Tuberculosis  of  mesenteric  glands. 

(2)  Tuberculosis  of  mesenteric  glands. 

(3)  Tuberculosis  of  mesenteric  glands,  with  intestinal 
tuberculosis. 

(4)  Tuberculosis  of  mesenteric  glands,  with  tubercles 
in  spleen  and  pleura. 

(5)  General  miliary  tuberculosis  of  lungs  and  meninges. 

(6)  Acute  general  miliary  tuberculosis. 

'2.  Of  the  workers  on  the  Royal  Commission  on  Tuber- 
culosis, Cobbett1  isolated  the  bacilli  from  sixty  cases,  and 
tabulated  his  results  as  follows  : 

1  Vol.  ii.  of  Appendix  to  vol.  i. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    111 


TABLE  X. 


Nature  of  Strain  of  Bacillus  isolated. 

Nature  of  Case. 

Number 
of  Cases. 

Bovine. 

Human. 

Irregu- 
lar. 

Human  ^ 
Bovine  on 

| 

Passage. 

Phthisis  with  tuber- 

cular sputum 

4 

1 

2 

— 

1 

Primary  pulmonary 

phthisis 

10 

— 

10 

— 

— 

General  tuberculosis 

1 

— 

1 

— 

Tuberculous      bron- 

chial glands 

4 

— 

2 

— 

.) 

Cervical  glands 

9 

3 

6 

— 

— 

Primary   abdominal 

glands  

19 

10 

8 

1 

— 

Joint        

10 

— 

9 

— 

1 

Testicle  and  kidney 

2 

— 

2 

— 

— 

Lupus      

1 

— 

— 

1 

— 

Total     .  . 

60 

14 

40 

2 

4 

Another  observer  gives  the  following  results  in  eight  cases 


TABLE  XI. 


Nature  of  Case. 

Age  in 
Years. 

Bovine 
Type. 

Human 
Type. 

Cervical  adenitis     
Tuberculous  tonsil  
Tuberculous  tonsil  and  glands 
Meningitis  and  glands   
Genito-urinary         
Miliary  tuberculosis        
Phthisis    

5 
5 
2 
3 
30 
21 

+ 
+ 

+ 

+ 

+ 

+ 
+ 

Phthisis,  peritonitis,  and  enteritis 

61 

1 

-1- 

Stewart  and  Ritchie  found  that  10  per  cent,  of  all 
cases  of  pulmonary  phthisis  refused  to  respond  to  diag- 
nostic test  No.  4  (vide  p.  104)  with  T.R.  of  human  origin, 


112  VACCINE  THERAPY 

and  now  believe  that  these  cases  are  due  to  infection  by 
the  bovine  variety ;  while  Ritchie  also  demonstrated 
by  means  of  test  Xo.  5  (p.  105)  that  out  of  eight  cases 
of  abdominal  tuberculosis,  five  were  due  to  infection  by 
the  bovine  type  and  three  to  the  human  ;  and  of  four 
cases  of  cervical  adenitis,  all  were  bovine  in  origin — 
results  which  agree  well  with  those  already  quoted. 
Taking  these  in  conjunction,  it  would  appear  that  adenitis 
is  slightly  more  frequently  due  to  the  bovine  than  to  the 
human  type,  and  that  this  holds  the  more  strongly  in 
the  case  of  young  children. 

Insufficient  observations  have  been  made  in  other 
varieties  of  tuberculosis,  excepting  the  pulmonary,  to 
justify  any  definite  conclusions  being  drawn. 

Spengler1  has  made  a  most  careful  study  of  112  cases, 
with  the  following  results.  Inasmuch  as  these  were  all 
cases  of  pulmonary  tuberculosis,  and  he  adopted  special 
methods,  his  results  must  stand  by  themselves. 

Sixty-eight  cases,  or  60-8  per  cent.,  showed  a  symbiotic 
working  of  the  human  and  bovine  types.  All  were 
chronic  cases. 

Twenty-two  cases,  or  19-6  per  cent.,  had  exclusively 
human  bacilli.  All  showed  fever,  and  offered  a  bad 
prognosis. 

Six  cases,  or  5-3  per  cent.,  had  almost  exclusively 
bovine  bacilli.  All  suffered  from  fever,  but  with  a  better 
prognosis  than  those  infected  by  the  human  variety  alone. 

Sixteen  cases,  or  14  3  per  cent.,  showed  only  '  splitter  ' 
(see  Appendix),  but  no  bacilli.  Of  these — 

Seven  had  only  human  bacilli  '  splitter  '  ; 
One  had  only  bovine  bacilli  '  splitter  '  ; 
Eight  had  both  human  and  bovine  bacilli  '  splitter.' 
1   Wien.  Klin.  Rundschau,  No.  33,  1906. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    113 

He  considers  that  the  two  varieties,  human  and  bovine, 
are  antagonistic  in  action,  causing  a  chronic  course. 
Those  cases  where  only  one  variety  is  found  are  the 
most  virulent  and  difficult  to  treat,  and  of  these  the 
human  is  more  virulent  than  the  bovine.  He  also  con- 
siders that  they  require  different  immunizing  agents,  and 
therefore  that  in  cases  where  both  varieties  are  present 
iti  s  necessary  to  determine  which  has  the  greater  signi- 
ficance, and  to  attack  that  one  with  the  appropriate  agent. 


IV.  CHOICE  OF  TUBERCULIN  APPROPRIATE  TO  A  GIVEN 

CASE. 

Assuming  for  the  time  being  the  possibility  of  deter- 
mining the  variety  of  the  bacillus  infecting  any  given 
case,  it  becomes  necessary  to  consider  which  is  the  appro- 
priate tuberculin  to  employ. 

Spengler  in  Germany,  Pottenger  in  America,  and  Raw 
in  this  country,  argue  as  follows  :  Romburg  and  Behring 
have  shown  that  cattle,  which  are  for  practical  purposes 
immune  against  the  human  variety,  can  be  most  com- 
pletely immunized  against  infection  by  the  bovine  type 
by  inoculation  with  the  human  type  ;  therefore,  con- 
versely, human  beings  can  be  best  immunized  against 
infection  by  the  human  type  by  means  of  tuberculin  of 
bovine  origin,  and  vice  versa.  Theoretical  objections  to 
this  reasoning  are  : 

1.  That  bovines  and  humans  are  not  quite  on  a  par  ; 
the  human  type  cannot  produce  generalized  tuberculosis 
in  bovines,  but  the  bovine  type  can  and  does  in  humans. 

2.  That  this  is  opposed  to  all  the  theories  of  immunity, 
and  still  more  opposed  to  all  the  experiences  of  vaccine 
therapy  with  other  organisms,  which  has  demonstrated 


114  VACCINE  THERAPY 

the  great  advantages  possessed  by  a  vaccine  of  the 
patient's  own  organisms,  even  over  one  of  the  same 
identical  organism  from  another  source.  This  would 
seem  to  indicate  clearly  that  not  only  is  a  tuberculin  of 
bovine  origin  inappropriate  to  an  infection  by  the  human 
type,  but  that  a  tuberculin  prepared  from  the  patient's 
own  organism  will  have  a  definite  advantage  over  a 
tuberculin  prepared  from  the  same  variety  from  any 
other  source. 

However,  an  ounce  of  practice  is  better  than  a  ton 
of  theory,  and  the  results  of  these  observers'  practical 
experience  require  consideration.  Acting,  then,  upon  the 
theory  that  the  human  and  bovine  types  of  the  bacillus 
are  opposed  to  each  other  in  every  way,  and  that  a 
human  tvpe  infection  is  best  combated  by  a  tuberculin 
of  bovine  origin,  and  vice  versa,  Spengler  devised  a 
system  of  therapy  (uncontrolled,  of  course,  by  opsonic 
index  determinations)  upon  the  following  lines  :  Having 
determined  the  variety  of  organism  at  work  by  means 
of  laboratory  and  clinical  observations,  he  gives  an  injec- 
tion of  a  diagnostic  dose  of  bacillary  emulsion  from  the 
other  variety  of  bacillus.  If  the  diagnosis  is  correct  the 
temperature,  if  elevated,  usually  falls,  and  the  patient 
will  declare  that  he  feels  better  ;  if,  on  the  other  hand. 
the  diagnosis  is  wrong,  then  the  remedy  acts  as  a  toxin, 
and  the  patient  experiences  an  increase  in  the  symptoms. 

When  the  patient  feels  better  after  the  injection  of 
a  vaccine,  this  preparation  may  be  taken  as  the  vaccine 
suited  to  the  case,  and  may  be  used  therapeutically. 
After  one  has  been  used  for  some  time  the  other  is  em- 
ployed, till  the  patient  is  immunized  to  both.  In  proof 
of  the  antagonistic  working  of  these  two  vaccines,  and 
what  seems  to  speak  very  much  for  this  therapy,  is  the 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    115 

fact,  adduced  by  Pottenger,1  that  if  one  preparation  is 
injected,  and  it  proves  to  be  the  toxin  for  the  patient 
instead  of  the  vaccine  (as  Spengler  calls  the  one  which 
does  not  act  toxically),  a  dose  of  the  other  may  be  injected 
at  once,  and  it  will  serve  to  counteract  the  toxic  action 
of  the  first  preparation.  (See  Figs.  28  A  and  B,  loc.  cit.) 

This  therapy  has  proved  very  successful  in  the  treat- 
ment of  fevering  cases,  and  also  in  the  treatment  of  such 
complications  as  tuberculosis  of  the  larynx,  intestines, 
and  kidney.  While  admitting  the  full  importance  that 
must  necessarily  be  attached  to  the  opinions  and  clinical 
experience  of  such  observers  as  Spengler  and  Pottenger, 
it  must  be  pointed  out  that  the  value  of  this  method  over 
the  older  one  has  not  been  actually  demonstrated  by 
comparative  statistics. 

Theoretically,  several  criticisms  may  be  made  against 
it  upon  a  priori  reasoning  : 

1.  It  is  opposed  to  all  experience  in  other  bacillary 
infections,  as  mentioned  before. 

2.  Spengler's  statistics  show  that  in  60-8  per  cent,  of 
all  cases  of  phthisis  there  is  a  symbiotic  working  of  human 
and  bovine  bacilli.     Therefore  in   60-8  per  cent,  of  all 
cases  this  therapy  results  in  the  simultaneous  administra- 
tion of  the  toxin  to  one  of  the  organisms  at  work  and  of 
the  antitoxin  to  the  other.     Thus  in  time  the  infection 
should  be  reduced  to  a  simple  one  by  one  variety,  which 
Spengler  himself  says  always  affords  the  worst  prognosis. 
It  is  true  that  afterwards  the  patient  is  immunized  to  the 
other  variety   as   well,    but   only  after  some  time   has 
elapsed. 

3.  That  the  toxin  of  one  variety  of  bacillus  is  the  better 
neutralized  by  the  antitoxin  elaborated  in  response  to  the 

1  'Pulmonary  Tuberculosis,'  p.  179. 

8—2 


116  VACCINE  THERAPY 

injection  of  the  other  variety  of  bacillus  is  no  proof  that 

the  more  powerful  ant  {bactericidal  substances  for  the  one 

variety  are  elaborated  in  response  to  injections  of  the 

other  variety.     Of  course  it  may  be  so,  but  it-i   s  not 

necessarily  so  ;   and  it   may  well   be  that  the  general 

reaction  obtained  by  the  injection  of  a  diagnostic  dose 

of  the  tuberculin  homologous  to  the  infecting  variety  of 

bacillus  is  a  response  to  the  toxic  products  formed  by  the 

death  of  the  bacilli  at  the  infected  focus,  and  so  a  measure 

of  the  resultant  bacteriolysis.     That  a  fall  of  temperature 

will  now  result  upon  inoculation  with  a  vaccine  of  the 

other  variety  of  bacillus  is  still  explicable  upon  Spengler's 

observation  that  the  toxins  of  the  one  are  neutralized 

best   by   the   antitoxins   elaborated   in   response   to   an 

injection  of  the  other  variety. 

There  is  some  evidence  to  support  this  possible  ex- 
planation.      On  p.  93  of  the  first    edition    the    author 
announced  that  he  was  conducting  a  series  of  cases  upon 
new  lines.     For  over  a  year  past  he  has  been  treating 
cases  of  adenitis,  pulmonary  phthisis,  and  ocular  tubercu- 
losis with  a  vaccine  containing  the   T.R.'s   of  human 
and  bovine  origin  mixed  in  equal  proportions.     Accord- 
ing to  Spengler's  view,  the  two  should  have  neutralized 
each  other's  action,  and  practically  no  effect  have  been 
produced.    Actually  the  results  have  appeared  to  be  so 
markedly  superior  to  any  he  had  previously  obtained 
that  the  use  of  the  ordinary  T.R.  has  been  completely 
given  up  in  favour  of  this  mixture.     The  series  of  cases 
treated  is,  however,  too  small  as  yet  to  enable  one  to  speak 
definitely  as  to  the  real  relative  value  of  the  method.     It 
is,  however,  hoped  that  other  observers  will  give  this  pro- 
cedure a  fair  trial,  obviating,  as  it  does,  the  necessity  of 
determining  the  variety  of  bacillus  at  work. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    117 

Stone  and  Miller,1  in  a  most  thoughtful  paper,  have 
drawn  attention  to  other  theoretical  considerations 
relative  to  immunization  by  means  of  the  tubercle 
bacillus  and  its  products.  They  tabulate  the  various 
preparations  as  follows.  Of  course,  either  the  human 
or  the  bovine  strain  may  be  the  source  for  each  : 

(Old  tuberculin  (Koch)      }  Productive  of 

A.  loxic  media  pro- 1  purified  Old  tuberculin  antitoxic 

ducts      ..      . .  [Bouillon  nitrate  (Denys)j    immunity. 

(New  T.R.  (Koch):   part]  , 

B.  Endotoxic  cellu-J          cellular  product          I  Productive  ot 

lar  products  ..  1  Bacillary  emulsion:  total  |  anttbactenal 
cellular  product  immunity. 

They  then  point  out  that,  inasmuch  as  the  protective 
influence  of  the  tuberculins  of  Class  A.  is  largely  anti- 
toxic and  not  bacterial,  it  would  seem  that  the  use  of  the 
filtrate  products  would  bring  the  most  benefit  in  cases 
suffering  from  pure  tuberculous  toxaemia  ;  but  toxaemia 
is  not  a  prominent  feature  of  uncomplicated  tuberculosis — 
at  least,  in  early  stages.  How  important  it  may  be  in 
advanced  cases  remains  to  be  settled.  Without  secondary 
organisms  (influenza  bacillus,  pneumococcus,  staphy- 
loeoccus,  and  streptococcus)  it  is  probable  that  toxic 
features  with  softening  and  dissolution  of  tissue  would  be 
a  much  less  important  factor  in  the  course  of  the  disease. 
Maragliano  having  shown  that  in  antitoxic  value  the 
serum  of  man  is  much  greater  than  the  serum  of  cow, 
goat,  or  horse,  but  in  antibacterial  power  that  the  re- 
verse is  the  case,  it  would  appear  that  in  man  the  attempt 
should  first  be  made  to  raise  the  antibacterial  value  of 
his  serum,  since  normally  this  is  lower  than  the  relative 
immunity  existing  towards  the  products  of  the  germ. 

1  Medical  Record,  March  28,  1908. 


118  VACCINE  THERAPY 

They  therefore  suggest  that  better  results  than  at 
present  obtained  might  be  secured  by  employing  a  com- 
bination of  bacillary  emulsion  with  bouillon  filtrate 
(Denys). 

V.  CONDUCT  OF  CASE  OF  PULMONARY  TUBERCULOSIS 

UNDERGOING    VACCINE    THERAPY. 

Assuming  that  the  diagnosis  of  tuberculosis  has  been 
duly  made,  the  variety  of  bacillus  at  work  determined, 
either  by  direct  or  indirect  means,  and  the  variety  of 
tuberculin  to  be  employed  decided  upon,  the  important 
question  remains,  shall  the  physician  rely  entirely  upon 
clinical  symptoms  as  his  guide,  and  employ  his  remedies 
rather  according  to  rule  of  thumb,  or  shall  he  be  guided 
by  determinations  of  the  opsonic  index?  As  will  be 
shown  in  Section  6  of  this  chapter,  Spengler,  Trudeau, 
Pottenger,  and  many  others  have  achieved  brilliant  re- 
sults, relying  upon  clinical  signs  alone,  and  employing 
doses  of  such  magnitude  and  at  such  intervals  as  are 
utterly  opposed  to  opsonic  principles.  Pottenger1  says  : 
'  If  the  negative  phase  were  as  important  as  Wright 
maintains,  we  would  have  killed  our  patients  by  the 
dosage  which  we  have  been  employing.  On  the  con- 
trary, those  who  have  used  tuberculin  and  its  allies  in- 
telligently, depending  upon  clinical  symptoms  and  local 
signs  as  the  guide  to  dosage,  have  been  able  to  produce 
the  best  results  that  have  been  obtained  in  the  treatment 
of  this  disease.  If  a  negative  phase  does  follow  every 
injection  of  tuberculin  vaccine,  we  must  assume  that  it  is 
of  less  importance  than  has  been  attributed  to  it.  While 
we  would  in  no  way  minimize  the  value  of  Wright's  work, 
— for  we  believe  it  furnishes  us  a  key  by  which  we  may 
1  '  Pulmonary  Tuberculosis,'  p.  197. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    119 

solve  many  of  the  problems  associated  with  the  phe- 
nomena of  immunity  and  the  treatment  of  infectious 
diseases — yet  we  do  not  believe  that  the  fact  that  many 
careful  clinicians  are  not  so  situated  as  to  be  able  to  avail 
themselves  of  the  knowledge  obtained  by  estimating  the 
opsonic  content  of  the  blood  should  deter  them  from 
giving  their  patients  the  b3nefit  of  intelligent  treatment 
by  specific  products  made  from  the  tubercle  bacillus.  It 
must  be  said,  however,  that  an  increased  experience 
seems  to  show  that  results  may  be  obtained  with  smaller 
doses  than  we  have  been  wont  to  employ.'  This  is  the 
opinion  of  a  thoroughly  scientific  and  unprejudiced 
mind  ;  yet  there  is  one  obvious  comment  to  be  made  : 
the  clinical  knowledge  and  the  power  of  accurate  obser- 
vation brought  to  bear  by  such  famous  specialists  as 
these  is  as  rare  as,  or  even  rarer  than,  the  capacity  for 
determining  the  opsonic  index  accurately,  and  the 
observations  needed  are  little,  if  any,  less  laborious.  The 
one  is  as  difficult  for  the  busy  general  practitioner  as 
the  other,  and  while  he  can  have  the  index  determined 
for  him,  he  cannot  himself  spare  the  time  even  to  acquire 
the  special  clinical  knowledge,  much  less  to  employ  it, 
in  the  case  of  every  phthisical  patient.  With  a  disease 
so  widespread  as  phthisis,  discussion  of  ideals  is  of  little 
use  to  the  many  ;  the  treatment  of  the  vast  majority  of 
cases  is,  and  probably  will  remain,  in  the  hands  of  the 
general  practitioner.  And  I  do  not  propose  to  discuss  the 
relative  merits  of  treatment  according  to  clinical  signs, 
as  practised  by  famous  specialists,  and  of  which  statistical 
results  are  available,  and  of  treatment  guided  by  de- 
termination of  the  opsonio  index,  also  by  specialists, 
and  of  which  sufficient  statistical  results  are  as  yet  lacking. 
The  last  word  has  as  yet  by  no  means  been  said  as  to 


120  VACCINE  THERAPY 

the  vaccine  therapy  of  pulmonary  tuberculosis.  Opsonic 
methods  have  taught  valuable  lessons,  and  will  probably 
teach  more,  but  there  is  an  undoubted  danger  of  overesti- 
mating the  importance  of  opsonic-index  estimations,  for, 
after  all,  opsonin  is  only  one  of  the  protective  substances 
elaborated  by  the  body,  and  of  its  importance  in  the  various 
infections  relative  to  the  other  immunizing  agents  we  as  yet 
know  nothing.  The  more  especially  true  does  this  appear 
to  be  in  the  case  of  the  tubercle  bacillus  and  phthisis. 

The  pure  clinician  will  continue  for  the  present  to  conduct 
his  procedure  under  the  guidance  of  clinical  symptoms, 
correcting  his  judgment  by  the  lessons  of  opsonic  methods. 
especially  as  regards  dosage  ;  the  opsonic  expert  will 
continue  along  opsonic  lines,  but  be  ready  to  modify  his 
present  opinions,  while  the  happy  few  who  are  possessed 
of  both  capabilities  will  probably  elaborate  methods  to 
supersede  those  of  both  the  others.  It  remains  for  the 
general  practitioner  to  decide  whether  he  will  disregard 
the  solemn  warnings  of  Wright,1  and,  while  paying  due 
regard  to  the  lessons  learnt  from  opsonic  methods  as 
regards  dosage,  rely  upon  his  powers  of  clinical  observa- 
tion, or  distrusting  his  own  powers  and  fearing  untoward 
results,  rely  upon  the  index  determinations  of  a  practised 
pathologist  as  his  guide.  The  financial  position  of  the 
patient  will  need  to  be  considered.  Should  it  be  capable 
of  bearing  the  strain,  I  think  that  in  the  present  state  of 
our  knowledge  the  best  results  can  only  be  expected  in 
every  case  under  the  guidance  of  the  opsonic  index,  and 
the  physician  will  be  well  advised  who  has  this  estimated 
every  week.  Good  results  are,  however,  often  to  be 
obtained  without  it,  and  inability  to  secure  its  guidance, 
either  from  financial  reasons  or  otherwise,  should  not 
1  Practitioner,  May,  1908. 


121 


deter  the  physician  from  giving  the  patient  the  benefit  of 
intelligent  treatment  by  specific  products  under  the 
guidance  of  clinical  symptoms  alone. 

TEMPERATURE  AS  A  GUIDE  IN  TUBERCULIN  THERAPY. 

The  statement  used  to  be  made  that  temperature  and 
pulse  bore  no  relation  soever  to  opsonic  index  ;  this  has 

CHART  XI.  (A.  C.  INMAN). 


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Temperature 
Opsonic  index 


This  chart  shows  how  temperature  and  opsonic  index  were  correlated 
in  a  case  of  pulmonary  phthisis.  The  two  will  be  seen  to  have  moved 
together  but  in  reverse  directions,  a  more  or  less  constant  phenomena. 

now  been  shown  to  be  quite  wrong.  The  negative  phase 
resultant  upon  the  injection  of  any  bacterial  vaccine  is, 
as  a  rule,  ushered  in  by  rise  of  temperature  (see  Chart  XI.), 
while  the  observations  of  Wright  himself,  in  septicsemic 
cases,  and  of  Latham,  Spitta  and  Inman,1  in  pyrexial 
1  Proceedings  of  the  Eoyal  Society  of  Medicine,  April,  1908. 


122  VACCINE  THERAPY 

and  apyrexial  phthisis,  clearly  show  that  the  opsonic  index 
fluctuates  with  the  temperature,  but  in  an  inverse  direc- 
tion. The  latter  observers  also  state  that  (1)  when  the 
temperature  has  been  fluctuating  from  97°  F.  to  98-4°  F., 
and  then  remains  level  at  98°  F.,  the  opsonic  index  rises ; 
(2)  when  the  temperature,  previously  level  and  normal,  or 
subnormal,  rises  to  99°  F.,  the  index  falls;  (3)  when  the 
temperature  is  persistently  high  the  index  is  persistently 
low  ;  (4)  when  the  temperature,  although  remaining  at 
about  the  same  high  level,  fluctuates  to  a  less  degree, 
there  is  an  improvement  in  the  opsonic  index. 

It  is  partly  to  auto-inoculations  that  these  rises  of 
temperature  are  to  be  ascribed,  and  the  importance  of 
either  obviating  or  controlling  the  auto-inoculations  by 
rest  in  bed  and  various  therapeutic  measures,  such  as 
increasing  the  coagulability  of  the  blood  by  doses  of 
calcium  salts,  becomes  more  than  ever  apparent. 

IMMUNIZATION  UNDER  GUIDANCE  OF  CLINICAL  SYMPTOMS. 

Such  measures  having  been  taken  for  the  good  of  the 
patient  as  clinical  experience  has  decided  to  be  appropriate, 
such  as  rest  in  bed,  good  food,  and  plenty  of  fresh  air, 
immunization  may  be  proceeded  with,  employing  one  or 
other  of  the  various  preparations  of  tuberculin,  as  follows  : 

T.A.  (Old  Tuberculin  Koch}. — This,  as  said  before,  is 
one  of  the  toxic  media  products,  and  is  now  chiefly  em- 
ployed for  the  diagnostic  test.  It  may  be  made  from 
either  human  or  bovine  strain,  the  latter  being  known  as 
P.T.A.  It  is  used  therapeutically  as  follows  : 

For  patients  in  the  first  and  second  stages,  in  whom 
prognosis  is  still  good,  and  who  are  free  from  fever,  the 
initial  dose  is  from  0-0001  c.c.  to  0-001  c.c.,  to  be  gradually 
increased  by  the  same  amount,  and  given  every  third  or 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    123 

fourth  day,  according  to  symptoms,  until  0-005  c.c.  has 
been  given,  when  the  increase  may  be  by  0-002  c.c.,  until 
0-01  c.c.  is  reached,  when  the  increase  may  be  more  rapid. 
A  feeling  of  nervousness,  malaise,  or  aching,  either  with 
or  without  a  slight  rise  of  temperature,  is  to  be  taken  as 
a  sign  of  reaction.  The  dose  should  then  not  be  repeated 
until  this  has  disappeared,  and  the  amount  should  not  be 
increased  until  this  amount,  when  injected,  fails  to 
produce  these  symptoms.  If  all  goes  well,  the  dose  may 
be  increased  thus  :  0-015,  0-02,  0-03,  0-04,  0-06,  0-08  c.c., 
given  at  properly  spaced  intervals  ;  but  this  should  not  be 
attempted  by  one  who  does  not  understand  the  remedy 
well.  Sometimes  patients  are  very  sensitive  to  tuber- 
culin, and  the  dose  can  then  only  be  increased  very 
cautiously,  it  taking  even  one  or  two  months  to  attain 
a  dosage  of  0-001  c.c. 

In  cases  in  the  third  stage  the  initial  dose  is  0-00001  c.c., 
and  it  will  often  be  found  impossible  to  raise  the  dose 
beyond  0-001  c.c.  to  0-01  c.c.  in  such  cases  without  pro- 
ducing a  reaction. 

In  almost  all  cases  the  maximum  dose  should  be  re- 
peated several  times  at  increasing  intervals  of  weeks  after 
the  patient  is  apparently  cured.  Bandelier  and  Roepke1 
state  that,  as  experience  increases,  the  centra-indications 
to  this  line  of  treatment  grow  fewer  and  fewer,  and  that 
they  have  treated  with  success,  or,  at  any  rate,  marked 
improvement,  advanced  cases  with  hectic  fever,  purulent 
expectoration,  cavities  in  the  lungs,  anaemia,  and  emacia- 
tion. 

Tuberculin  (Denys)  is,  like  the  above,  a  toxic  medium 
product.  It  is  a  nitrate  made  from  the  bouillon  on  which 
the  bacilli  have  grown,  and  is  prepared  without  being 

1  Lelir.  der  Spezif.  Diag.  u.  Ther.  der  Tuber.,  Wtirzburg,  1908. 


124  VACCINE  THERAPY 

subject  to  heat,  and  is  not  concentrated  like  Koch's  old 
tuberculin. 

The  pure  tuberculin  is  taken,  and  seven  successive 
dilutions  made,  each  of  a  tenth  of  the  strength  of  the 
preceding,  so  that  the  final,  or  Xo.  7  dilution,  contains 
0-0000001  c.c.  of  the  original  tuberculin  in  each  c.c.  This 
is  the  initial  dose  in  febrile  cases  ;  in  a  febrile  case  1  c.c. 
of  the  No.  4  dilution  =  0-0001  c.c.  of  the  original  tuber- 
culin, is  employed. 

In  either  case  the  increase  in  dosage  is  by  0-1  c.c.  at 
intervals  of  three  to  four  days  for  the  smaller  doses  ;  as 
the  higher  doses  are  reached,  five  or  six  days  must  elapse, 
and  for  the  last  three  or  four  doses,  when  the  pure  tuber- 
culin is  being  used,  intervals  of  a  week  or  ten  days  must 
be  allowed.  The  final  dose  is  1  c.c.  of  pure  tuberculin. 
If  no  intolerance  be  evidenced,  the  course  of  treatment 
will  extend  over  six  months,  but  when  reaction  occurs  it 
may  need  a  year.  If  it  does  appear,  it  is  necessary  to  await 
its  disappearance,  and  begin  again  with  half  that  dose. 
Reactions  occur  the  more  readily  at  doses  between  0-0001 
and  0-001  c.c.  Denys  refers  to  2,000  cases  as  having  been 
treated  successfully  by  him  according  to  this  procedure. 

T.O.  (human)  and  P.T.O.  (bovine)  correspond  in  pro- 
perties to  the  old  tuberculin.  They  are  composed  of 
the  toxic  products  removed  by  treating  the  comminuted 
bacilli  with  water  in  the  preparation  of  T.R. 

Spengler's  P.T.O.  is  not  concentrated  by  heat  ;  he  finds 
it  much  less  toxic  for  human  infections  than  the  corre- 
sponding preparation  from  the  human  type,  and  at  the 
same  time  more  active  in  the  stimulation  of  the  machinery 
of  immunization,  as  measured  by  the  power  to  increase 
the  specific  agglutinins  of  the  blood. 

The  procedure  is  exactly  the  same  as  for  T. A.     Spengler, 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    125 

however,  considers  the  least  feeling  of  warmth  at  the  site 
of  injection  as  sufficient  to  negative  a  fresh  injection  until 
this  sign  of  reaction  has  subsided.  Bandelier  and  Roepke 
(foe.  cit.}  report  satisfactory  results  in  178  cases.  Fever 
and  the  presence  of  mixed  infection  are  not  contra-indica- 
tions  to  its  use,  and  Spengler  believes  that  only  patients 
in  extremis,  or  with  very  acute  pulmonary  phthisis,  are 
beyond  its  reach. 

T.R.  (human)  and  P.T.R.  (bovine)  are  endotoxic  cellu- 
lar products  prepared  from  the  human  and  bovine  types 
respectively.  They  are  probably  the  mildest  of  all  the 
forms  of  tuberculin,  and  are  productive  of  antibacterial, 
and  only  to  a  slight  extent  of  antitoxic  immunity.  They 
are,  therefore,  especially  suitable  for  the  treatment  of 
patients  who  are  very  sensitive  to  T.A.  or  T.O.,  and  may 
be  used  to  pave  the  way  for  the  use  of  these  latter.  The 
initial  dose  is  0-0001  to  0-0002  c.c.,  and  may  be  given  every 
other  day  at  first.  It  can  usually  be  doubled  at  each  dose, 
until  0-01  c.c.  of  the  original  has  been  given.  After  this 
the  injections  should  be  further  apart,  and  the  increase  in 
dosage  be  as  follows  :  0-015,  0-025,  0-035,  0-06,  0-08,  0- 1  c.c. 
After  0.5  c.c.  has  been  given  the  dose  should  be  given 
only  once  a  week  ;  0- 1  c.c.  is  rarely  exceeded.  At  the  least 
sign  of  reaction  the  dose  must  be  withheld  until  all  reaction 
has  disappeared,  and  it  must  not  be  increased  until  the 
patient  fails  to  react  to  the  dose  which  has  once  caused  a 
reaction. 

B.E.  (human)  and  P.B.E.  (bovine)  are  total  cellular 
products,  and  consist  of  an  emulsion  in  50  per  cent, 
glycerine  of  the  pulverized  bodies  of  the  bacilli,  without 
prior  removal  of  toxins  soluble  in  distilled  water.  They 
contain  5  milligrams  of  bacillary  substance  per  c.c  ,  and 
are  probably  the  most  active  of  all  the  preparations.  The 


126  VACCINE  THERAPY 

objection  to  them  is  the  difficulty  of  absorption  of  the 
bodies  of  the  bacilli,  which  may  remain  in  the  tissues,  act 
as  mechanical  irritants,  and  cause  a  pseudo-abscess  con- 
taining sterile  sero-purulent  fluid.  The  initial  dose  is 
0  0005  c.c.,  and  is  repeated  every  second  or  third  day,  each 
time  increasing  the  amount  given  by  two  or  three  times 
the  amount  previously  given.  When  a  reaction  is  pro- 
duced, the  injections  are  given  at  longer  intervals — say, 
every  six  to  eight  days.  They  are  increased  till  1  to  2  c.c. 
of  the  original  is  reached,  but  these  large  doses  are  given 
only  every  two  to  three  weeks,  on  account  of  the  slowness 
of  absorption.  In  pyrexial  cases  the  initial  dose  is  not 
more  than  one-tenth  of  that  indicated  above.  These 
preparations  are  the  ones  most  favoured  by  Spengler, 
and  are  employed  by  him  as  indicated  on  p.  114. 

IMMUNIZATION  UNDER  THE  GUIDANCE  or  THE  OPSONIC 

INDEX. 

Despite  the  criticisms  levelled  against  the  accuracy  of 
present  methods  of  determining  the  opsonic  index,  this 
must  be  admitted,  even  by  the  most  biassed,  as  the  most 
scientific  means  of  attempting  to  secure  immunity. 
Even  should  the  time  and  amount  of  dosage  of  any  par- 
ticular injection  not  be  determined  by  prior  determination 
of  the  index,  a  study  of  the  whole  opsonic  curve,  taken 
in  conjunction  with  the  temperature  chart,  clinical  signs, 
and  general  condition  of  the  patient,  will  afford  the  most 
valuable  information  as  to  the  progress  of  the  patient 
and  his  immunizing  responses.  The  first  essential  that 
must  be  secured  before  full  use  can  be  made  of  this 
method  is  arrest,  as  complete  as  possible,  of  all  auto- 
inoculations  by  rest,  physical  and  mental,  and  other 
therapeutic  measures,  among  which  may  be  mentioned 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    127 

administration  of  full  doses  of  calcium  salts.  A  reduced 
and  regular  temperature,  and  steady  opsonic  index — it 
may  be  at  a  level  higher  or  lower  than  normal — will 
indicate  cessation  of  auto-inoculations  and  return  to  a 
more  or  less  strictly  localized  infection.  The  index 
having  been  estimated  at  the  same  time  upon  two  or 
three  consecutive  days,  not  only  to  the  human,  but  also 
to  the  bovine  type,  and  the  maintenance  of  a  steady 
level  assured,  a  minimal  dose  of,  say,  0-00001  c  c.  of  the 
appropriate  tuberculin  is  given.  Which  is  the  appro- 
priate tuberculin  must  be  considered.  Raw1  says,  for 
pulmonary  phthisis  the  T.R.  of  bovine  origin.  Spengler 
(vide  p.  114)  determines  it  experimentally  by  the  ad- 
ministration of  a  diagnostic  dose  of  tuberculin  of  known 
origin  and  the  observation  of  the  temperature  reaction. 
The  author,  in  view  of  Spengler 's  bacteriological  studies, 
whereby  he  shows  (p.  112)  that  68  per  cent,  of  all  pul- 
monary cases  were  infected  by  both  the  human  and 
bovine  types,  and  a  recent  limited  clinical  experience, 
would  urge  that  a  mixture  of  human  and  bovine  T.R.'s 
in  equal  amounts  will  best  suit  the  greater  majority  of 
cases,  and  will  suit  the  remainder  as  well  as  any  other. 

Whether  the  view  of  the  antagonism  of  the  two  strains 
be  correct  or  not,  the  advisability  of  estimating  the  index 
towards  both  strains  is  obvious.  This,  then,  is  done  upon 
the  day  following  the  injection,  and,  if  possible,  upon  each 
day  up  to  the  tenth,  that  the  precise  amount  of  reaction 
and  duration  of  negative  phase  may  be  estimated.  As  to 
how  the  results  are  to  be  interpreted  as  a  measure  of 
dosage,  etc.,  see  p.  26. 

The  object  now  is  to  maintain  the  index  at  as  high 

1  Lancet,  February  15,  1908,  p.  481,  etc. 


128  VACCINE  THERAPY 

and  steady  a  level  as  possible,  and  to  bring  as  full  a 
supply  as  possible  of  this  actively  immunizing  blood  to 
the  infected  focus.  The  injections  are  therefore  repeated 
at  suitable  intervals,  which  may  vary  from  ten  to  twenty- 
one  days,  and  in  adequate  doses,  and  the  coagulability 
of  the  blood  diminished,  if  necessary,  by  doses  of  citric 
acid.  The  dosage  is  steadily  increased  as  indicated  by 
the  index,  but  is  rarely  raised  above  0-0002  c.c.  In 
apyrexial  cases  where  there  are  no  auto-inoculations 
occurring,  this  treatment  may  be  conducted  while  the 
patient  is  going  about  his  daily  work. 

In  cases  complicated  by  secondary  infections,  much 
better  results  than  are  now  obtained  will  probably  be 
secured  by  a  simultaneous  attack  upon  the  staphylo- 
cocci,  streptococci,  pneumococci,  micrococcus  catarrhalis, 
Friedlander's  bacillus,  B.  inftuenzce,  etc.,  which  may  be 
present. 


IMMUNIZATION  BY  MEANS  OF  AUTO  -  INOCULATIONS 
INDUCED  BY  MEANS  OF  A  SCHEME  OF  GRADUATED 
EXERCISE. 

has  been  warmly  advocated  by  Patterson.1  Inman 2 
has  studied  the  scientific  aspect  of  this  question,  and 
finds  the  explanation  of  the  excellent  results  achieved  by 
Patterson  in  the  effects  produced  upon  the  opsonic  index. 
It  would  appear  that  much  benefit  accrues  to  convalescent 
patients  by  means  of  such  exercises,  carefully  graduated 
under  the  guidance  of  temperature  chart,  clinical  signs, 
and  opsonic  index,  and  that  a  more  speedy  and  complete 
cure  is  effected. 

1  Lancet,  January  25,  1908,  p.  216.  2  Ibid:,  p.  220. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    129 

IMMUNIZATION  ACCORDING  TO  THE  LESSONS  LEARNT  FROM 
A  STUDY  OF  OPSONIC  METHODS,  BUT  NOT  UNDER 
THE  GUIDANCE  OF  THE  OPSONIC  INDEX. 

This  obviously  must  be  the  resort  of  many  busy  general 
practitioners,  who  have  neither  the  time  nor  skill  necessary 
for  doing  the  index  themselves,  and  whose  patients  are 
not  in  such  a  financial  position  as  to  warrant  the  work 
being  done  by  a  highly-trained  pathologist.  That  the 
best  results  will  be  secured  is  an  obvious  impossibility, 
but  this  is  no  reason  why  the  patient  should  be  de- 
prived of  the  benefits  likely  to  accrue  from  a  course  of 
therapeutic  inoculations  intelligently  conducted.  Even 
pyrexial  cases,  and  others  where  auto-inoculations  are 
occurring,  can  derive  little  harm,  and  may  derive  much 
good.  A  thoroughly  safe  and  reliable  scheme  of  treat- 
ment remains  to  be  worked  out,  but  the  observations 
of  Spengler,  that  pyrexia  due  to  the  human  strain  may 
be  reduced  by  a  vaccine  of  bovine  origin,  and  the  sug- 
gestion of  Stone  to  attack  simultaneously  the  bacilli 
and  their  excreted  toxin  by  the  combination  of  the 
appropriate  T.R.  with,  say,  Denys'  tuberculin  deserve 
full  consideration.  My  own  procedure  at  present  (con- 
trolled, however,  by  index  determinations)  is  to  use 
mixed  human  and  bovine  T.R.'s  for  all  cases  ;  and  in 
those  where  toxaemia  is  an  important  factor  to  combine 
minute  doses  of  Denys'  tuberculin  with  the  T.R.'s.  I 
can  only  say  that  a  very  limited  experience  has  given  the 
utmost  satisfaction. 

In  apyrexial  cases,  then,  the  following  provisional 
scheme  might  be  laid  down  for  use  without  index  deter- 
minations, but  controlled  by  common  sense  and  close 
clinical  observation  : 

9 


130  VACCINE  THERAPY 

Begin  with  a  dose  of  0-00001  c.c.  mixed  human  and 
bovine  T.R.  Repeat  this  in  seventeen  to  twenty-one 
days,  unless  contra-indicated,  and  again  after  a  similar 
interval.  Fourteen  days  later  give  0-00002  c.c.  of  the 
same  mixture,  and  repeat  in  fourteen  days.  If  satisfac- 
tory improvement,  continue  for  one  or  two  more 
similar  doses  at  similar  intervals.  If  neither  improve- 
ment nor  the  reverse,  increase  dose  to  0-00003  c.c.  at 
twelve  days'  intervals.  If  ill  is  resulting,  carefully 
consider  whether  it  is  due  to  the  treatment  or  in  the 
natural  course  of  things,  and  decide  whether  to  continue 
or  not. 

In  this  way  a  dose  of  0-0001  to  0-0002  c.c.,  repeated  at 
ten  days'  intervals,  may  be  attained  in  about  nine  months. 
If  cure  has  apparently  resulted,  then  slowly  diminishing 
doses  may  well  be  employed  at  lengthening  intervals  for 
another  six  months. 

In  pyrexial  cases  take  all  possible  steps  to  reduce 
pyrexia  and  control  auto-inoculation  ;  then  proceed  as 
before,  with  extra  caution,  combining,  however,  with  the 
T.R.'s  quantities  of  Denys'  tuberculin,  very  minute  at 
first,  but  increasing  at  each  dose  in  much  greater  ratio 
than  the  T.R.  Thus,  the  initial  dose  may  be  0-0000001  c.c., 
going  on  as  follows  :  0-0000002  c.c.,  0-0000003  c.c., 
0-0000006  c.c.,  0-000001  c.c.,  0-000002  c.c.,  and  so  on 
until  ultimately  a  dosage  of  even  0-001  c.c.  has  been 
attained  in  combination  with  0-0001  to  0-0002  c.c.  of 
each  T.R, 

This  scheme,  guided  by  common  sense  and  controlled 
by  close  clinical  observation,  will,  I  think,  be  found  per- 
fectly safe,  and  productive  of  good  results. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    131 

RESULTS  OF  VACCINE  THERAPY  IN  PULMONARY 
TUBERCULOSIS. 

A.  By  Methods  controlled  by  Clinical  Symptoms. — 
Pottenger,1  after  pointing  out  that  culture  products  are 
to  be  used  in  tuberculosis,  and  that  they  are  not  repre- 
sented as  having  any  influence  over  dead  tissue,  or  as 
being  able  to  regenerate  cells  that  have  been  destroyed, 
and  therefore  that  their  proper  sphere  is  in  incipient 
cases  before  mixed  infection  or  breaking  down  with 
absorption  occurs,  gives  the  following  statistics  of  the 
comparative  results  obtained  in  first-stage  tuberculosis 
by  sanatorium  methods  pure  and  simple,  and  by  sana- 
torium methods  supplemented  by  tuberculin  therapy 
according  to  the  methods  outlined  on  p.  125  : 

Four  observers  treated  611  first-stage  cases  with  all 
the  advantages  of  sanatorium  treatment,  and  apparently 
cured  391,  or  64  per  cent. 

Ten  observers  supplemented  sanatorium  treatment 
with  tuberculin  therapy  in  589  similar  cases,  of  which 
496,  or  84-2  per  cent.,  were  apparently  cured. 

Pottenger  considers  that  these  are  quite  sufficient  cases 
upon  which  to  base  an  opinion,  and  considers  that  culture 
products  certainly  stand  the  test  and  accomplish  that 
for  which  they  are  recommended — namely,  the  cure  of 
pure  tuberculosis. 

TRUDEAU'S  RESULTS. 

From  1890  to  1901  Trudeau  in  America  employed 
inoculation  treatment  in  cases  of  pulmonary  phthisis. 
The  adjoined  table  is  a  comparison  of  the  results  obtained 

1  '  Pulmonary  Tuberculosis,'  p.  343. 

9—2 


132 


VACCINE  THERAPY 


by  pure  sanatorial  measures  with  those  supplemented  by 
inoculations  of  tuberculin. 

TABLE  XII. 


(1)  Cases  treated  (Non- 
Tuberculin). 

(2)  Cases  treated  with 
Tuberculin. 

Advantage  to  (2) 
over  (1). 

1,367 

Alive,  38'0  per  cent. 

Dead,  36'6 

^ 

143 

Alive,  58'0  per  cent. 

Dead,  33  "0 
s 

20  -0  per  cent. 
3'6 

Balance  untraced 


INCIPIENT  CASES  ONLY. 


(1)  Cases  treated  (Xon- 
Tuberculin). 

(2)  Cases  treated  with 
Tuberculin. 

Advantage  to  (2) 
over  (1). 

Alive,  61  '0  per  cent. 

Alive,  76-7  per  cent. 

15'  7  per  cent. 

Turban's  results  at  Davos  Platz l  have  been  as  follows  : 

In  the  first  stage  his  results  were  such  as  led  him  to 

say  :  '  Now,  if  we  compare  the  results  in  early  cases  in 

which  tubercle  bacilli  were  found  in  the  sputum,   the 

result  is  substantially  in  favour  of  tuberculin  treatment. 

'  Of  cases  in  the  second  stage  48  were  treated  with 
tuberculin  ;  9  died  within  two  years  of  treatment ;  3  died 
within  three  years  of  treatment  and  more  ;  16  were  alive 
six  years  after  treatment ;  5  more  alive  five  years  after 
treatment ;  3  more  alive  four  years  after  treatment.  In 
all,  36  were  alive.  Thus,  of  48  cases  36  were  alive  and 
12  dead.  Of  152  cases  treated  in  the  ordinary  way, 
45  were  dead  and  107  alive ;  but  the  figures  show  greatly 
in  favour  of  tuberculin  treatment,  because  of  the  107  alive 
a  great  number  (49)  were  under  treatment  more  than 
one  or  two  years. 

1  Weicker.  Beit.  z.  Frage  der  VolksJieilstaetten,  p.  22. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    133 

'  Of  cases  in  Stage  III.,  21  cases  were  treated  with  tuber- 
culin. In  8  there  was  tuberculous  laryngitis  ;  9  cases 
survived  five  years  ;  3  more  survived  four  years.  Only 
5  out  of  21 — or  25  per  cent. — died  within  two  years  ; 
3  were  quite  well  six  years  after.  In  all  5  were  well. 

'  Of  cases  treated  in  other  ways,  61  out  of  84  died,  and  of 
these,  41 — or  nearly  50  per  cent. — died  within  two  years. 
Compare  this  with  25  per  cent,  under  tuberculin  treatment. ' 

Thus,  even  in  the  second  and  third  stages  of  the 
disease,  which  do  not  strictly  fall  within  the  zone  of 
tuberculin  treatment,  a  great  advantage  is  seen  to  exist 
on  the  side  of  vaccine  therapy.  As  regards  mixed  in- 
fection, which  Pottenger  points  out  exists  in  cases  dis- 
playing fever  of  even  mild  degree,  and  which  doubtless 
has  its  influence  on  the  tuberculous  process  in  many 
cases  where  no  rise  of  temperature  exists,  he  says  r1 
'  I  do  not  doubt  but  that  the  true  remedy  will  be  obtained 
in  a  vaccine  made  from  the  cultures  taken  from  the 
strain  of  the  micro-organism  found  in  each  individual 
patient.  The  results  which  we  have  had  so  far  in  our 
endeavours  to  treat  in  this  manner  are  very  encouraging.' 
Tuberculin  alone  can  no  more  be  expected  to  work  im- 
possibilities than  can  antidiphtheritic  serum  in  moribund 
cases  of  diphtheria. 

RESULTS  ACHIEVED  BY  VACCINE  THERAPY  CONTROLLED 
BY  DETERMINATIONS  OF  THE  OPSONIC  INDEX,  OR 
ACCORDING  TO  THE  METHODS  WHICH  EXPERIENCE 
IN  OPSONIC  WORK  INDICATED. 

The  opsonic  method  has  been  upon  trial  for  far  too 
short  a  time  to  enable  anything  like  reliable  statistics 
1  P.  261,  loc.  cit. 


134  VACCINE  THERAPY 

to  be  collected.  Nothing  more  than  the  impressions 
gained  as  to  its  value  by  different  observers  can  be 
adduced  in  its  favour.  The  most  complete  series  of 
cases  so  far  published  are  those  of  Turton,1  who  describes 
the  results  obtained  in  26  cases  of  tuberculosis  of  lungs 
and  pleura,  in  19  of  which  control  by  the  index  was 
employed. 

In  6  early  cases  without  great  lung  destruction  or 
severe  constitutional  disturbance  the  disease  was  appar- 
ently arrested,  there  being  no  abnormal  physical  signs  or 
symptoms  for  six  months.  Their  gain  in  weight  re- 
spectively was  19,  13,  17|,  3,  12£,  14  pounds. 

In  6  cases,  of  which  2  were  far  advanced,  with  great 
loss  of  weight  and  constitutional  disturbance,  great  im- 
provement occurred.  Symptoms,  however,  were  still 
present,  or  six  months  had  not  elapsed  since  apparent 
cure.  Their  gain  in  weight  respectively  was  35£,  13,  17, 
7,  23,  and  38  pounds. 

In  6  cases  there  was  some  improvement  in  general 
health,  and  the  signs  and  symptoms  were  ameliorated, 
but  the  result  was  not  entirely  satisfactory.  These  were 
most  severe  cases  of  long  standing,  with  considerable 
lung  destruction  or  some  complication,  their  gain  in 
weight  respectively  3,  3£,  0,  5,  8,  0  pounds. 

In  3  cases  there  was  little  or  no  improvement,  but 
they  were  very  unfavourable  cases,  the  home  surroundings 
being  very  unsatisfactory,  disease  extensive,  and  general 
health  rapidly  failing. 

Five  cases  died  either  during  or  after  suspension  of 
treatment,  but  were  practically  hopeless  from  the  first, 
and  were  only  injected  as  a  last  resort. 

All  these  cases  were  treated  out  of  hospital,  in  some 
1  '  International  Clinics '  (eighteenth  series),  vol.  ii.,  p.  23. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    135 

cases  with  very  unsatisfactory  home  surroundings  ;  and 
almost  all  had  to  carry  on  their  usual  occupations. 
Besides  the  tuberculin,  cod-liver  oil  and  occasional  tonics 
were  the  only  remedies  used. 

In  the  successful  cases  the  clinical  results  are  great 
improvement  in  general  health,  gradual  fall  in  evening 
temperature,  return  of  appetite,  and  increase  in  weight. 
The  cough  gradually  becomes  less  troublesome,  and  the 
sputum  reduced  in  quantity  ;  the  tubercle  bacilli  become 
fewer,  and  finally  disappear.  The  physical  signs  become 
less  marked,  and  where  lung  destruction  has  been  great 
are  replaced  by  signs  of  fibroid  lung.  In  slighter  cases 
all  physical  signs  may  disappear.  While  the  patient  is 
doing  well,  a  gradual  fall  of  the  evening  temperature  is 
one  of  the  most  striking  features.  In  some  cases  a  fall 
of  a  degree  or  so  occurs  during  the  several  days  imme- 
diately following  an  injection,  to  rise  again  slowly  as  the 
next  becomes  due,  after  which  it  again  falls.  This  is 
only  seen  in  some  cases,  and,  Turton  says,  is  independent 
of  the  index.  The  temperature  he  does  not  consider  to 
be  a  trustworthy  guide.  His  doses  varied  from  0-0001  to 
0-001  c.c.,  chronic  cases  having  the  larger  doses  at  the 
longer  intervals — say,  0-0005  c.c.  every  twelve  to  twenty 
days — while  acute  cases  did  better  on  a  dose  of  0-0002  c.c., 
repeated  in  from  seven  to  twelve  days.  It  cannot  be 
too  strongly  emphasized  that,  if  an  accurate  estimate 
of  the  true  value  of  index  determinations  in  the  treat- 
ment of  pulmonary  tuberculosis  is  to  be  formed,  observers 
must  divide  their  cases  up  methodically  into  classes,  as 
is  done  by  Trudeau,  Pottenger,  Turban,  and  others,  and 
the  subsequent  histories  of  the  cases  carefully  watched  for 
a  term  of  years. 


136 


VACCINE  THERAPY 


THE  INDICES  OF  '  CURED  '  SANATORIUM  CASES  AND  THE 
QUESTION  OF  THEIR  INJECTION. 

Lawson  and  Stewart1  examined  twenty-five  cases  of 
pulmonary  phthisis  '  cures.'  In  five  of  these  the  index 
was  between  1-1  and  0-9  ;  in  the  other  twenty  it  was  0-8, 
or  under.  Twenty-three  of  these  elected  to  be  injected, 
with  the  results  shown  in  Table  XIII. 

TABLE  XIII. 


Case. 


Index  before 
Injection. 


Index  after  Course 
of  Injections. 


Number  of 
Injections. 


1 

1-0 

1-1 

1 

2 

0-9         1-4 

3 

3 

0-9 

1-4 

3 

4 

09 

1-2 

3 

5 

0-8 

1-4 

3 

6 

0-8 

1-0 

4 

7 

0-8 

1-3 

5 

8 

0-8 

1-1 

1 

9 

0-8 

1-0 

3 

10 

0-8 

1-2 

2 

11 

0-7 

M 

4 

12 

0-7 

1-5 

3 

13 

0-7 

10 

2 

14 

0-7 

1-3 

3 

15 

0-7 

1-3 

4 

16 

0-7 

1-2 

3 

17 

0-7 

1-3 

3 

18 

0-7 

1-3 

4 

19 

0-7 

1-3 

4 

20 

0-5         1-1 

5 

21 

0-5         0-8 

2 

22 

0-5         1-5 

4 

23 

0-5         1-1 

5 

The  additional  rise  in  antibacterial  substances  obtained 
by  the  inoculations  subsequent  to  a  long  course  of  climatic 

1  Lancet,  December  9,  1905,  p.  1683. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    137 

and  sanatorium  treatment  is  very  striking.  Whether 
such  cases  with  abnormally  low  indices  are  especially 
liable  to  relapse  we  know  not,  but  Lawson  is  strongly  of 
the  opinion  that  no  case  of  apparently  cured  phthisis  with 
a  low  index  should  be  discharged  from  the  sanatorium 
until  the  index  has  been  raised. 


VACCINE  THERAPY  IN  OTHER  FORMS  OF  TUBERCULOSIS. 

1.  Tuberculous  Adenitis. — Of  the  frequency  of  tuber- 
cular adenitis,  often  unrecognized  in  children,  there  is 
little  need  to  dilate.  Thus,  MacConkey  and  MacFadyen 
found  virulent  tubercle  bacilli  present,  usually  in  the 
mesenteric  glands,  of  about  25  per  cent,  of  children  who 
died  from  non-tuberculous  causes.  In  infants  dying  of 
tuberculosis  Steiner  and  Newieter  found  the  lymph 
glands  affected  299  times  in  302  post-mortems,  the 
bronchial  glands  being  involved  286  times.  Rilliet  and 
Barthez  found  lymphatic  glands  involved  248  times  in 
312  cases  ;  and  Northrup  every  time  in  125  cases.  Not 
only  are  the  glands  involved,  but  they  are  the  first  to 
show  the  disease  in  a  large  majority  of  cases,  if  this  can 
be  inferred  from  the  fact  that  the  glands  show  the  most 
advanced  processes.  All  cases  of  tuberculosis  of  the 
glands,  however,  do  not  show  tuberculosis  elsewhere,  nor 
are  all  enlarged  lymphatic  glands  tuberculous  (about  60 
per  cent.  are).  Steffen,  however,  says  :  '  Healthy  lymph 
glands  are  not  attacked  by  tuberculosis.  They  are  pre- 
disposed thereto  when  they  are  swollen,  succulent,  and 
infiltrated,  and  in  a  condition  of  hyperplasia.'  While 
Osier  says  :  '  A  special  predisposing  factor  in  lymphatic 
tuberculosis  is  a  catarrhal  inflammation  of  the  mucous 
membranes,  which  in  itself  excites  a  slight  adenitis.' 


138  VACCINE  THERAPY 

The  extreme  importance  of  putting  all  children,  and 
especially  infants,  under  the  best  hygienic  conditions  is 
thus  obvious,  while  the  advisability  of  applying  the 
tuberculin  test,  best  by  means  of  Pirquet's  cutaneous 
reaction,  in  all  cases  where  glands  are  chronically  enlarged, 
the  nutritional  condition  bad,  and  the  child  unduly  pale 
or  peevish,  deserves  earnest  consideration,  in  view  of  the 
fact  that  a  large  percentage  of  those  who  have  enlarged 
glands  during  childhood  develop  tuberculosis  in  later 
life. 

Variety  of  the  Bacillus  Responsible. — From  the  bacterio- 
logical findings  upon  pp.  110,  111  and  112,  it  appears  that 
in  thirty-nine  cases  the  human  type  was  isolated  eighteen 
times  and  the  bovine  twenty-one.  In  so  far  as  one  can 
deduce  from  so  few  cases,  it  thus  appears  that  two  varieties 
are  found  with  about  equal  frequency.  It  is  therefore 
obvious  that  if  either  a  T.R.  of  human  origin,  or  that  of 
bovine  origin,  be  employed  invariably,  it  will,  strictly,  be 
the  most  appropriate  tuberculin  in  only  50  per  cent,  of  the 
cases.  It  therefore  becomes  necessary  either  to  determine 
which  is  the  right  tuberculin,  according  to  one  or  other  of 
the  methods  outlined  on  p.  109,  or  to  adopt  the  suggestion 
of  the  author,  and  always  employ  a  mixture  of  the  two 
T.R.'s  in  equal  proportions  ;  this  latter  is  the  less  scientific, 
but  is  perhaps  the  more  easily  workable  scheme. 

Once  the  diagnosis  has  been  made  that  enlarged  glands 
are  tuberculous,  it  becomes  incumbent  not  only  to  place 
the  child  under  the  best  possible  hygienic  conditions,  but 
also  to  submit  it  to  a  course  of  tuberculin  treatment,  in 
view  of  the  almost  uniformly  successful  results  thereby 
obtained,  and  so  prevent  subsequent  caseation  and  sinus 
formation,  and  perhaps  pulmonary  or  some  other  serious 
form  of  tuberculosis. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    139 

Wright,  White,1  Western,2  Riviere,3  Loveday  and 
Ramsbottom,4  and  many  others,  have  published  most 
satisfactory  results,  despite  the  sole  employment  of  T.R. 
of  human  origin,  which,  as  said  before,  cannot  have  been 
always  appropriate. 

When  caseation  is  present,  prolonged  treatment  may 
be  necessary,  and  perhaps  surgical  interference.  If  lique- 
faction be  a  feature,  an  extensive  operation  may  be  some- 
times obviated  by  the  preliminary  raising  of  the  index  to 
1  or  over,  and  the  passage  of  a  tenotome  into  the  caseous 
mass  and  the  expression  of  the  contents. 

Sinuses  may  be  aided  by  the  additional  treatment  of  a 
vaccine  of  the  secondarily  infecting  organisms,  scraping, 
and  perhaps  the  application  of  hypertonic  solutions  of 
common  salt  and  citric  acid,  to  assist  transudation  oi 
lymph  rich  in  opsonin. 

As  in  the  case  of  pulmonary  tuberculosis,  the  best 
results  will  almost  certainly  be  attained  under  the  guidance 
of  the  opsonic  index.  Should  this  not  be  available,  then 
an  initial  dose  of  0-00001  c.c.  of  each  T.R.  may  be  repeated, 
and  increased  at  such  intervals  as  the  clinical  condition 
indicates,  much  upon  the  lines  already  laid  down  under 
pulmonary  tuberculosis. 

2.  Tuberculosis  of  Bones  and  Joints. — Far  too  few 
observations  as  to  the  variety  of  bacillus  at  work  have  as 
yet  been  made  to  enable  any  definite  conclusion  to  be 
drawn,  but  it  may  be  noted  that  in  the  instance  of 
all  ten  cases  cited  on  p.  Ill  the  human  variety  was 
found. 

For  a  case  of  early  joint  disease,  splints,  rest,  Bier's 

1  Journal  of  Medical  Science,  Dublin,  September  2,  1907,  p.  161. 

2  Lancet,  November  23,  1907,  p.  1449. 

3  British  Medical  Journal,  October  26,  1907,  p.  1131. 

4  Medical  Chronicle,  June,  1908,  p.  145. 


140 


VACCINE  THERAPY 


congestion,  and  tuberculin  will  probably  suffice  to  effect 
cure.  Should  the  disease  be  advanced,  and  the  surgeon 
decide  upon  scraping  or  excision,  a  preliminary  raising  of 
the  index  by  means  of  tuberculin  will  minimize  the  risk 
of  dissemination,  and  a  continuation  of  such  treatment 
after  the  operation  will  expedite  the  cure.  It  may,  how- 
ever, be  noted  that  cases  of  this  kind,  so  advanced  that 
even  amputation  was  advocated,  have  cleared  up  in 
such  a  marvellous  manner  under  tuberculin  and  the 
usual  therapeutic  measures  that  no  case  need  be  con- 
sidered hopeless  until  such  measures  have  received  trial 
(see  Chart  XII.,  for  instance,  of  such  a  case). 

CHAET  XII.  (Dr.  J.  W.  E.). 

SEVERE  TUBERCULOUS  SYNOVITIS  OF  KNEE,     FIRST  FOUR  MONTHS  OF 
TREATMENT. 


WeeKS  I 


8       9      10 


12      !3      W      (5 


V 


Injecftcnso 
3 
S 


Fluid  from  joint  when  inoculated  into  a  guinea-pig  produced  typical 
generalized  tuberculosis  in  eight  weeks.  Complete  cure  in  six  months,"  with 
perfect  mobility  of  joint. 

Secondary  infections  will,  of  course,  require  their  appro- 
priate vaccines. 

Western  (loc.  cit.)  gives  his  results  in  twenty-six  cases  as 
follows  : 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS     141 

Fourteen  cases  were  cured. 

Five  cases  showed  marked  improvement,  and  were  still 
under  treatment. 

Two  cases  showed  slight  improvement. 

Five  cases  showed  no  improvement,  but  two  of  these 
were  senile  cases  in  patients  over  sixty. 

In  young  subjects  and  early  cases  cure  and  good  move- 
ment may  be  expected  ;  but  where  there  is  much  destruc- 
tion of  tissue  and  sinuses  are  present,  progress  is  slow  and 
movement  may  be  considerably  limited. 

Raw1  records  his  experience  in  twenty-seven  cases, 
mostly  of  a  chronic  or  subacute  variety  :  '  The  cases 
where  the  best  results  were  obtained  were  those  in  which 
there  was  some  suppuration  or  sinus  leading  directly 
down  to  tuberculous  disease.  In  cases  of  pulpy  disease 
of  the  joints  there  was,  in  many  instances,  marked 
diminution  in  the  size  of  the  joints  with  absence  of 
inflammation  and  more  movement.' 

Turton  treated  five  cases,  one  being  of  the  elbow,  the 
other  four  spinal.  The  former  was  completely  cured.  Of 
the  spinal  cases  one  had  had  three  operations,  and  there 
were  sinuses  in  the  back,  loin,  and  iliac  region.  Despite 
secondary  infection  with  Staphylococcus  albus,  the  patient 
did  extremely  well,  gained  two  stone  in  weight,  and  has 
been  at  work  for  over  a  year.  In  the  second,  an  early 
case,  the  disease  was  apparently  arrested.  The  third  was 
an  old  case,  and  was  only  under  treatment  a  short  time, 
when  improved  general  health  resulted.  The  last  case  was 
hopeless  from  the  first,  and  died  of  lardaceous  disease. 

Painter2  reported  on  eleven  cases  as  follows.  He 
excludes  two  cases  as  being  unfair.  The  other  nine  were 

1  Lancet,  February  15,  1908,  p.  480. 

2  Boston  Medical  and  Surgical  Journal,  October  31,  1907,  p.  621. 


142  VACCINE  THERAPY 

all  advanced  cases,  usually  with  mixed  infections.  Two 
cases  were  extraordinarily  improved,  one  considerably  so  ; 
four  not  at  all.  He  considers  the  method  worthy  of  a 
longer  trial,  and  believes  that  with  a  more  judicious 
selection  of  cases  better  results  would  be  forthcoming. 

In  my  own  experience  these  cases  do  extremely  well, 
especially  if  treatment  be  simultaneouly  directed  against 
any  secondary  infection  ;  the  cases  which  do  not  do  well 
are  those  in  which  other  parts  are  also  affected,  where 
there  is  marked  wasting  or  signs  of  lardaceous  disease, 
or  where  secondary  infections  cannot  be  controlled  owing 
to  neglect  on  the  part  of  the  patient. 


LUPUS  AND  OTHER  TUBERCULIDES  OF  THE  SKIN. 

In  no  other  branch  of  tuberculin  therapy  have  such 
absolutely  discordant  results  been  obtained.  Upon  the 
one  hand,  we  have  the  following  opinion  of  Reyn  and 
Petersen  :x  '  The  results  of  the  sole  treatment  with  T.R. 
have  been  very  bad.  We  could  not  in  any  of  the  cases 
see  any  improvement  at  all  following  treatment  accord- 
ing to  Wright's  method.  In  the  most  fortunate  cases 
the  affection  remained  stationary  ;  in  most  of  the  cases 
it  became  worse.  We  wish  especially  to  call  attention 
to  the  fact  that  in  two  out  of  the  three  early  cases  the 
disease  spread  remarkably  quickly  during  the  T.R.  treat- 
ment. We,  therefore,  feel  bound  to  dissuade  prac- 
titioners from  employing  this  method  as  a  sole  treatment 
for  lupus  vulgaris,  both  in  old  cases  and  in  fresh  apparently 
benign  cases.' 

Upon  the  other  hand,  Raw  :2  '  Twenty-four  cases  of 
lupus  have  been  treated,  and  it  is  here  that  the  very 
1  Lancet,  April  4,  1908,  p.  1004.  2  Ibid.,  p.  481. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    143 

-ISfeM 


144  VACCINE  THERAPY 

best  results  of  tuberculin  are  obtained.  All  stages  of  the 
disease  seemed  to  respond  rapidly  to  injections,  and  in 
all  the  cases  in  which  I  have  used  tuberculin  without 
any  other  treatment,  such  as  scraping  or  medication, 
the  ulcerated  surface  has  healed  with  a  firm  cicatrix, 
and  in  only  two  instances  so  far  has  the  disease  re- 
curred.' 

Between  these  two  diametrically  opposed  opinions  are 
to  be  set  the  experience  of  Wright  and  of  Bulloch  and 
Western. 

Wright  finds  that  in  these  varieties  of  lupus  where  the 
skin  is  dry  and  scaly — so-called  lupus  psoriasis — tuber- 
culin is  of  little  avail ;  while  in  suppurating  lupus,  where 
mixed  infection  by  the  Staphylococcus  albus  is  present, 
good  results  can  only  be  achieved  by  a  simultaneous 
attack  upon  the  secondary  infection. 

Bulloch  and  Western  also  find  that  the  ulcerative 
type  does  much  the  best  with  tuberculin,  especially  if 
combined  with  fomentations.  Treatment  may  have  to 
be  very  prolonged,  and  is  best  continued  long  after  disease 
has  apparently  disappeared,  as  fall  of  index  seems  to 
predispose  to  a  renewed  attack. 

Whitfield's  results  have  been  disappointing. 

Western  (loc.  cit.)  records  the  successful  treatment  of 
two  cases  of  erythema  induratum,  one  presenting  ulcera- 
tion,  the  other  not. 

Whitfield l  finds  that  tuberculous  ulcers  have  done  well, 
even  though  in  some  cases  the  surroundings  have  been 
as  adverse  as  possible.  Of  two  cases  of  Bazin's  disease. 
one  apparently  completely  recovered  ;  the  other,  after 
improving  enormously  at  first,  relapsed,  and  seemed  to 
derive  little  benefit  from  further  treatment. 

1  Practitioner,  May,  1908,  p.  697. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS     145 

TUBEBCULOSIS    OF   THE    GENITO-URINARY    SYSTEM. 

Pardoe1  lays  stress  upon  the  frequency  and  non- 
recognition  of  this  form  of  tuberculosis,  and  especially  of 
that  of  the  bladder.  So  disappointing  have  been  the 
results  of  operative  treatment  and  of  all  kinds  of  bladder 
washes  and  instillations  that  he  declared  that  he  himself 
had  never  met  with  a  case  even  of  apparent  cure  of 
vesical  tuberculosis  by  such  means.  Tuberculin  treat- 
ment has  here  met  with  success  that  can  only  be  called 
brilliant.  Pardoe  himself  treated  twenty-one  cases  with 
tuberculin,  many  of  these  before  opsonic  work  was  known. 
Despite  this  fact,  and  the  certainty,  as  he  himself  admits, 
of  having  at  times  given  much  too  large  doses  and  at 
improper  intervals,  he  obtained  the  following  results  : 


TABLE  XIV. 

Per 

Cent. 


Cured  5  cases  out  of  21      24 
Greatly  improved  4  cases 
out  of  21         . .          . .   19 

43 


Per 

Cent. 


No    improvement    in    6 

cases  out  of  21  . .  28 

Death  in  6  cases  out  of  21  28 

56 


He,  however,  considers  that  tuberculin  should  never 
be  given  in  genito-urinary  cases  if  the  orifices  of  both 
ureters  are  infected. 

Other  observers  whose  work  has  been  guided  by 
opsonic  determinations  do  not  agree  with  this,  and  have 
obtained  even  more  encouraging  results  (Chart  No.  XIII., 
a  case  under  Dr.  Eyre,  affords  an  especially  good  example 
of  this).  Thus,  Western  (loc.  cit.)  says  that  where 
adequate  treatment  has  been  carried  out  good  results 
have  followed.  In  one  case  with  slight  ulceration  of  the 

1  Lancet,  December  16,  1905,  p.  1766. 

10 


146 


VACCINE  THERAPY 


trigone,  pain  and  frequency  of  micturition  with  blood 
and  bacilli  in  the  urine,  and  a  hard,  nodular  prostate,  all 
urinary  symptoms  disappeared  in  six  months,  though  the 
prostatic  condition  remained. 

Turton  (loc.  cit.)  treated  4  cases  of  tuberculous  kidney  ; 


CHART  XIV.   (J.  W.  E.). 


Weetel 


8       9       10       II       12      13      14      IS 


Dotted  line  =  percentage  of  pus  in  urine. 
Coutinuous  line=tubercolo-opBomc  i^dex. 

This  chart  exhibits  the  first  four  months'  result  of  treatment  in  a  very  bad 
case  of  renal  and  vesical  tuberculosis.  The  cystoscope  showed  advanced 
disease  of  the  right  kidney,  slightly  earlier  in  the  left  kidney,  and  advanced 
in  the  bladder.  The  patient  improved  greatly  under  treatment,  and  was 
alive  and  in  fair  health  two  years  from  the  commencement  of  treatment. 

1  died,  the  other  3  were  greatly  improved,  and,  in  Turton's 
opinion,  derived  very  great  benefit  from  the  injections, 
especially  as  in  2  of  these  all  the  resources  of  surgery  had 
been  exhausted. 

Western    (foe.    cit.)    records    15    cases    of    tuberculous 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    147 

epididymitis.  Of  these,  6  were  cured  in  from  three  to 
nine  months  ;  4  were  greatly  improved,  the  sinuses 
healed,  and  though  the  disease  was  still  evident,  the 
patients  were  able  to  go  about  ;  4  had  only  been  under 
treatment  less  than  two  months,  but  were  doing  well, 
and  1,  which  also  suffered  from  diffuse  pulmonary  phthisis, 
alone  derived  no  benefit.  Western  concludes  that  good 
results  may  be  expected,  even  when  the  disease  has 
broken  down  and  sinuses  are  present. 

The  importance  of  paying  due  attention  in  these  cases 
to  secondary  infections,  especially  by  the  Bacillus  coli 
communis,  can  hardly  be  overestimated. 

TUBERCULOSIS  OF  THE  INTESTINES. 

Very  little  use  appears  to  have  been  made  of  tuber- 
culin therapy  in  this  condition.  Turton  (loc.  cit.)  records 
the  following  remarkable  case  :  '  The  abdomen  was 
opened,  and  such  extensive  disease  found  of  the  caecum 
and  ileum  that  removal  was  impossible.  Thirty-eight 
injections  of  T.R.  and  twenty-one  of  B.C.C.  vaccine  were 
given  in  sixteen  months,  with  the  result  that  the  patient 
gained  16  pounds  in  weight,  and  the  tumour,  which  was 
the  size  of  a  goose's  egg,  entirely  disappeared.  The 
patient  has  been  back  at  work  over  a  year,  and  has  only 
very  rare  attacks  of  pain  very  mild  in  character. ' 

TUBERCULOUS  PERITONITIS. 

Here  excellent  results  have  been  obtained,  both  with  and 
without  laparotomy.  The  best  procedure  appears  to  be 
preliminary  raising  of  the  index  with  T.R.,  laparotomy, 
and,  after  allowing  the  full  effects  of  the  auto-inoculation 
induced  by  the  operation  to  pass  off,  resuming  tuberculin 

10—2 


148  VACCINE  THERAPY 

treatment.  Raw  (loc.  cit.)  records  his  results  in  eight 
cases,  four  being  of  the  dry  plastic  variety,  four  associated 
with  fluid  in  the  abdomen.  All  recovered,  and  were  dis- 
charged well  after  twelve  inoculations.  He  considers 
that  tuberculin  is  an  absolute  specific  in  cases  where  the 
disease  is  confined  to  the  abdomen.  Wright1  gave  the 
following  details  of  a  most  interesting  case  :  Laparotomv 
had  been  performed  two  months  previously,  without  any 
resultant  improvement.  A  temperature  of  100°  F.  per- 
sisted, the  wound  discharged,  and  the  condition  became 
desperate.  Under  T.R.  the  temperature  came  down  to 
normal  in  six  weeks,  and  in  three  months  the  patient  was 
discharged.  In  six  months  the  gain  in  weight  equalled  27 
pounds,  and  six  months  still  later  the  patient  was  seem- 
ingly perfectly  well. 

TUBERCULOUS  MENINGITIS. 

Even  in  this  extremely  grave  form  of  tuberculosis 
successes  have  been  reported.  It  is  not  to  be  supposed 
that  there  have  not  been  failures,  but,  on  the  other  hand, 
some  successes  also  have  not  yet  been  published. 

Buchanan  showed  before  the  Liverpool  Medical  Insti- 
tute on  December  5,  1907,  a  child  who  had  suffered  from 
tuberculous  meningitis,  and  recovered  after  an  illness  of 
four  weeks,  with  coma  for  eight  days.  The  symptoms 
were  classical,  Calmette's  test  reacted  positively,  and 
the  cerebro-spinal  fluid  contained  excess  of  lymphocytes. 
An  injection  of  0-000025  c.c.  T.R.  was  given  ;  the  child 
showed  almost  immediate  improvement,  and  gradually 
regained  consciousness.  Three  weeks  later  the  dose  was 
repeated.  Recovery  was  uninterrupted,  and  the  child 
was  quite  intelligent  and  able  to  run  about. 
1  Clinical  Journal,  November  9,  1904. 


INFECTIONS  BY  THE  TUBERCLE  BACILLUS    149 

Raw  (loc.  cit.)  relates  the  following  account  of  four  cases, 
which  exhibited  all  the  classical  symptoms  :  In  two,  tuber- 
culin had  no  effect,  and  the  children  died ;  in  the  other  two, 
all  the  symptoms  disappeared  after  four  injections,  and 
the  children  made  a  rapid  recovery. 

OCULAR  TUBERCULOSIS. 

My  experience  in  this  form  of  tuberculosis,  whether  of 
the  choroid,  iris,  or  cornea,  has  been  uniformly  favour- 
able during  the  past  twelve  months — i.e.,  since  my  adop- 
tion of  mixed  human  and  bovine  T.R.  as  the  immunizing 
agent.  Cases  for  which  clinical  experience  would  have 
indicated  a  course  of  six  or  nine  months'  treatment  with 
human  T.R.  have  recovered  instead  in  four  or  six.  Two 
cases — one  of  tuberculous  choroid  and  cornea,  the  other 
of  episcleritis,  with  tubercular  glands — are  making  ex- 
ceptional progress,  the  improved  general  condition  and 
increase  in  weight  being  also  very  marked.  No  other 
treatment  except  a  little  atropine  is  being  employed. 


CHAPTER  VII 

STAPHYLOCOCCAL  INFECTIONS 

THE  Staphylococcus  albus  and  aureus  may  be  the  cause 
of  inflammatory  and  suppurative  processes  in  various 
parts  of  the  body.  Among  acute  forms  of  infection  may 
be  instanced  Suppurative  Periostitis  and  Osteomyelitis, 
Ulcerative  Endocarditis,  Pleurisy,  Peritonitis  and  Men- 
ingitis, Carbuncle  and  Furuncle,  Endometritis,  and  various 
Pyaemic  conditions  ;  among  its  chronic  manifestations  are 
Acne,  Ulcers,  and  Sycosis.  It  may  also  secondarily  infect 
cases  due  to  tubercle,  Bacillus  coli  communis,  Bacillus 
typhosus,  and  streptococcus,  etc.  Its  relationship  to  chronic 
gleet  is  discussed  under  the  chapter  on  the  Gonococcus. 

ACNE. 

The  index  in  these  cases  is  consistently  subnormal, 
varying  from  0-2  to  0*8.  The  isolation  of  the  organism 
in  such  cases  has  already  been  dealt  with,  and  also  the 
method  of  preparation  of  the  vaccine.  This  organism  is 
an  especially  easy  one  to  deal  with  in  every  respect.  The 
response  to  injection  is  always  marked  by  such  definite 
clinical  reactions  that  frequent  estimations  of  the  index 
may,  as  a  rule,  be  dispensed  with ;  indeed,  some  venture 
to  do  without  them  altogether.  The  negative  phase  is 
nearly  always  indicated  by  a  crop  of  suppurative  foci, 
which,  however,  abort  in  a  day  or  two.  The  appearance 
of  a  second  crop  is  the  signal  for  a  fresh  injection,  which 

150 


STAPHYLOCOCCAL  INFECTIONS  151 

is  usually  required  at  intervals  of  fourteen  to  twenty-one 
days.  Personally,  however,  I  think  it  better  practice 
always  to  do  the  index  the  day  before  a  proposed  injection. 
A  very  suitable  dose  to  commence  with  is  250,000,000 
organisms,  except,  perhaps,  in  tropical  climates,  where, 
I  am  advised,  initial  doses  of  100,000,000  are  more  appro- 
priate. This  soon  requires  increasing  to  500,000,000  and 
750,000,000,  the  necessity  for  this  being  evidenced  by 
the  recurrence  of  mild  attacks.  Later  larger  doses  still 
may  be  necessary.  In  the  worst  case  of  acne  I  have  ever 
seen  doses  of  1,750,000,000  bacteria  were  given  towards 
the  end  of  treatment  at  fortnightly  intervals,  the  index 
then  remaining  steadily  between  0-9  and  1-2,  when  re- 
covery was  soon  completed.  It  is  well  to  note  that  very 
slight  cases  may  prove  extremely  obdurate,  especially 
if  the  general  health  of  the  patient  be  good  and  the  bowels 
require  no  regulation.  In  one  such  case — the  mildest 
that  I  have  had  under  my  care — a  very  confident  prog- 
nosis was  given,  with  the  result  that  in  six  months  little 
progress  had  been  made,  and  cure  was  only  secured  by 
the  use  of  a  dosage  of  4,000,000,000  at  ten  days'  intervals. 

In  the  case  of  deep-seated  foci  which  refuse  to  come  to 
a  head — acne  indurata — hyperaemia  by  means  of  dry- 
cupping  is  a  very  useful  adjuvant  to  the  vaccine  therapy. 

The  type  of  case  which  yields  the  least  satisfactory 
results  is  that  characterized  by  marked  oily  seborrhcea, 
abundant  comedo,  and  few  suppurative  foci.  Here 
especial  attention,  both  local  and  general,  will  require  to 
be  paid  to  the  seborrhcea  and  the  comedines  should  be 
systematically  expressed. 

Treatment  must  be  persisted  in  even  for  six  or  eight 
months,  until  not  only  do  fresh  foci  fail  to  appear,  but 
even  the  old  scars  have  begun  to  disappear.  Diminished 


152 


VACCINE  THEEAPY 


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STAPHYLOCOCCAL  INFECTIONS  153 

doses  at  prolonged  intervals  will  in  most  cases  complete 
the  cure. 

A  small  percentage  of  cases  remain  entirely  obdurate, 
while  others  relapse  after  apparent  cure.  In  these  latter 
it  is  well  to  supplement  a  fresh  course  of  vaccine  therapy 
with  yeast  or  iodopin  by  the  mouth  or  nuclein  sub- 
cutaneously.  As  a  rule,  the  best  result  will  be  secured  by 
the  use  of  an  '  autogenous  '  vaccine — i.e.,  one  prepared 
from  the  patient's  own  organisms.  This  especially  holds 
for  cases  of  '  acute  indurata.'  On  the  contrary,  those 
from  which  organisms  of  but  slight  virulence  and  feeble 
power  of  growth  are  obtained  do  best  with  a  vaccine 
prepared  from  a  more  virulent  strain.  Most  cases  will 
progress  very  satisfactorily  under  a  polyvalent,  stock 
vaccine. 

BOILS  AND  CARBUNCLES. 

The  results  recorded  by  many  observers  in  boils  and 
carbuncles,  of  which  the  greater  proportion  are  due  to 
1  aureus, '  have  been  uniformly  good.  Thus,  Whitfield1 
says  :  '  In  all  the  cases  of  furunculosis  which  I  have 
treated  I  have  obtained  complete,  and  up  to  the  present 
durable,  success.'  Western  :2  '  Nine  cases  of  furunculosis 
were  treated  with  '  aureus  '  vaccine  in  every  instance,  with 
completely  satisfactory  results.  All  the  cases  of  carbuncle 
were  ones  which,  in  spite  of  incision,  fomentations,  and 
local  antiseptics,  showed  no  adequate  attempt  at  repair  or 
healing,  yet  all  made  rapid  recovery.'  Hartwell  and  Lee3 
draw  the  following  conclusions  from  their  results  in  100 
cases  of  '  aureus '  infections  :  '  Treatment  with  vaccines 

1  Practitioner,  May,  1908,  p.  698. 

2  Lancet,  November  23,  1907,  p.  1449. 

3  Boston  Medical  and  Surgical  Journal,  vol.  cvii.,  No.  16,  p.  523. 


154  VACCINE  THERAPY 

i-;  the  most  effectual  treatment  for  boils  and  carbuncles. 
There  is  marked  diminution  in  the  pain  and  tenderness. 
After  twenty-four  hours  there  is  a  profuse  discharge, 
which  continues  till  the  focus  clears  up.  With  boils 
about  the  face,  the  especial  value  of  the  treatment  is  the 
prevention  of  scarring.  Although  the  vaccine  treatment 
does  not  prevent  recurrence,  cases  of  chronic  furuncu- 
losis  can  be  absolutely  controlled  by  occasional  inocula- 
tion.' The  initial  dose  is  from  100,000,000  to  250,000,000. 

SYCOSIS. 

Various  factors  tend  to  render  the  successful  treatment 
of  this  complaint  more  difficult  than  the  preceding.  The 
disease  is  a  very  chronic  one,  and  results  in  seriously 
diminished  powers  of  resistance  in  the  skin,  and  irrita- 
tion is  kept  up  by  local  conditions,  such  as  nasal  dis- 
charge and  dust  ;  the  organisms  are,  moreover,  difficult  of 
access  for  the  immunizing  lymph.  For  these  reasons 
relapse  is  also  liable  to  occur.  Depilation  by  the  '  X  rays  ' 
or  other  means  will  considerably  aid  in  the  cure,  but  even 
then  treatment  may  have  to  be  very  prolonged. 

PERIOSTITIS  AND  OSTEOMYELITIS. 

When  staphylococci  complicate  a  tubercular  infection, 
as  in  psoas  abscess,  fistula  '  in  ano?  joint  and  bone  disease, 
etc.,  vaccine  injections  prove  of  the  utmost  value  to  the 
surgeon.  Indeed,  I  have  seen  cases  which,  despite  re- 
peated operation,  persistently  refuse  to  get  well,  clear 
up  as  if  by  magic  after  two  or  three  injections  of  staphy- 
lococcal  vaccine  as  adjuvant  to  tuberculin.  Simple  acute 
infections  invariably  do  well,  but  long-continued  cases,  com- 
plicated by  lardaceous  disease,  are  not  nearly  so  hopeful. 


STAPHYLOCOCCAL  INFECTIONS  155 

SEPTICJEMIC  AND  PYJEMIC  CASES. 

Few  such  have  as  yet  been  recorded.  Whyte  l  details 
the  result  of  a  case  in  a  man  of  fifty-six,  with  varicose 
ulcers  of  the  leg  and  pyrexia,  as  high  as  104°,  of  three 
months'  duration,  with  occasional  rigors  and  night- 
sweats.  A  pure  culture  of  staphylococcus  was  obtained 
from  the  blood,  the  index  being  1-2.  An  injection  of 
250,000,000  was  given,  with  the  result  that  immediate 
improvement  began.  Next  day  the  index  was  0-7  ; 
subsequently  it  was  1-6,  1-8  ;  and  on  the  eighth  day  2-6. 
Upon  the  tenth  day  the  blood  was  sterile,  and  further 
treatment  was  unnecessary. 

Turton  (loc.  cit.)  records  three  cases.  One  of  pyaemia 
originated  in  a  septic  osteomyelitis.  There  was  a  septic 
temperature,  and  multiple  abscesses  formed  almost  daily. 
Three  injections  of  Staphylococcus  aureus  did  not  seem  to 
have  any  influence,  and  the  patient  died  nine  days  after 
the  first  injection. 

The  second  case  developed  septicaemia  a  week  after 
parturition.  The  temperature  was  102°  F.  for  five  nights. 
Two  injections  were  given  at  intervals  of  forty-eight  hours. 
Twenty-four  hours  after  the  second  injection  the  tempera- 
ture dropped  to  normal,  and  recovery  was  uninterrupted . 

The  third  case  was  subsequent  to  miscarriage.  The 
pulse  was  130,  temperature  104°  F.,  and  the  condition 
desperate.  Five  injections  were  given  at  intervals  of 
two  to  four  days.  She  improved  greatly,  and  eleven  days 
after  the  first  injection  temperature  was  normal.  Pul- 
monary embolism  unfortunately  supervened,  and  death 
resulted  twenty  days  after  the  commencement  of  treat- 
ment. 

1  Edinburgh  Medical  Journal,  December,  1907,  p.  555. 


156  VACCINE  THERAPY 

Wright1  also  records  a  very  interesting  case.  The 
patient  suffered  from  mitral  disease,  and  had  had  eight 
months  of  occasional  pyrexia,  with  pulmonary  infarction 
and  cerebral  embolism.  A  staphylococcus  of  somewhat 
aberrant  characteristics  was  cultivated  from  the  blood, 
and  an  '  autogenous  '  vaccine  prepared.  The  experience 
with  this  was  much  more  favourable  than  had  been  that 
with  a  stock  vaccine  previously  employed.  Six  injec- 
tions— three  of  5,000,000  and  three  of  10,000,000 — were 
given  under  the  guidance  of  the  opsonic  index.  The 
temperature  soon  became  normal,  and  complete  recovery 
ensued. 

Very  varying  dosages  have  been  employed  by  different 
observers.  Some  have  used  doses  as  low  as  5,000,000, 
others  as  high  as  1,000,000,000. 

In  these  septic«mic  cases  the  best  results  can  only  be 
expected  from  the  use  of  an  '  autogenous  '  vaccine,  ad- 
ministered under  the  guidance  of  the  opsonic  index. 
The  temperature  may  come  down  to  normal  after  a  single 
injection,  and  subsequent  rise  may  be  too  late  an  indica- 
tion of  the  necessity  for  fresh  inoculation,  while  a  per- 
sistent pyrexia  affords  no  indication  as  to  whether  the 
dosage  is  inadequate  or  the  patient  incapable  of  an 
immunizing  response. 

In  cases  where  index  determinations  cannot  be  made 
it  is  impossible  to  do  more  than  suggest  an  initial  dose 
of  10,000,000,  to  be  increased  next  day  if  no  fall  of 
temperature  result,  the  increases  to  be  continued  and 
doses  given  every  other  day  till  the  temperature  does  fall 
or  clinical  symptoms  suggest  that  the  patient  is  incapable 
of  response.  The  subsequent  course  of  treatment  will 
be  guided  by  the  temperature  and  clinical  condition. 
1  Lancet,  November  2,  1907,  p.  1217. 


CHAPTER  VIII 

THE  STREPTOCOCCUS 

STREPTOCOCCI,  like  staphylococci,  cause  inflammation  and 
suppuration  in  all  parts  of  the  body.  Till  quite  recently 
reliance  was  placed  upon  injections  of  antistreptococcic 
serum  in  such  cases  as  Erysipelas,  Pyaemia,  Puerperal 
Fever,  Periostitis,  and  Endocarditis.  The  frequent  failure 
of  this  treatment  is  now  explicable  owing  to  the  recogni- 
tion of  the  fact  that  the  streptococcus  is  not  a  single 
individual,  but  is  a  generic  name  for  a  large  and  very 
heterogeneous  class,  the  members  of  which  are  capable 
of  producing  the  most  varied  forms  of  lesion. 

Gordon l  suggested  the  classification  of  the  streptococci 
according  to  the  reactions  they  displaced  in  the  following 
nine  media  :  Litmus  milk,  neutral  red  agar,  and  broth 
containing  1  to  2  per  cent,  of,  respectively,  saccharose, 
lactose,  raffinose,  inulin,  salicin,  coniferin,  and  mannite. 

Andrews  and  Horder  have  extended  this  work  and, 
combining  with  these  nine  tests  observations  as  to  growth 
on  gelatine  at  20°  C.  morphology  in  broth,  and  patho- 
genesis  towards  the  mouse,  have  divided  the  streptococci 
into  the  following  types  (see  Table  on  page  158). 

Other  modifications  in,  and  additions  to,  these  tests 
have  been  made,  but  no  satisfactory  method  of  classifica- 
tion has  yet  been  devised. 

1  Local  Government  Board's  Reports,  1903-04. 
157 


158 


VACCINE  THERAPY 


The  importance  of  the  bearing  that  the  variety  of  the 
bacillus  present  in  any  given  case  of  streptococcal  infection 
has  upon  the  choice  of  a  vaccine  appropriate  to  the  case 
is  evident. 

Horder1  investigated  this  question  in  twenty-eight 
cases  of  ulcerative  endocarditis,  of  which  eighteen  proved 
to  be  due  to  streptococci.  The  majority  of  these  proved 
to  belong  to  the  '  salivarius,'  and  'fsecalis  '  types,  indicating 
that  infection  has  occurred  either  via  the  tonsil  or  intestine. 

TABLE  XV. 


S.  Pyo- 
geues. 

S.  Sali- 
varius. 

S.  Angi- 
nosus. 

S.  Ffeca- 
lis. 

Pneumo- 
coccus. 

Milk  clot 

Neutral  red 

•• 

+ 
+ 

+ 
± 

+ 
± 

+ 

Saccharose 

+ 

+ 

+ 

+ 

+ 

Lactose 

+ 

+ 

+ 

+ 

+ 

Baffinose 

.  . 

+ 

.  . 

.  . 

+ 

Inulin 

.  . 

.  . 

.  . 

.  . 

+ 

Salicin 

± 

.  . 

+ 

Coniferin 

.  . 

.  . 

.  . 

+ 

.  . 

Mannite 

.  . 

.  . 

+ 

Growth   in    gelatine   at 
20°  C. 

+ 

+ 

Morphology  in  broth   .  . 
Pathogenesis  for  mouse 

longus 

+ 

brevis 

longus 

+ 

brevis 

brevis 

+ 

+  =  Formation  of  clot  in  milk,  and  acid  in  other  media. 

The  cases  in  which  the  Streptococcus  pyogenes  longus  occurs 
are  relatively  few,  and  belong  to  the  fulminant  type,  being 
usually  rapidly  fatal.  Why  the  other  cases  run  such  a 
prolonged  course  and  exhibit  so  few  signs  of  auto-intoxi- 
cation, although  bacteria  may  be  present  in  the  blood  in 
large  numbers,  is  evident  from  consideration  of  this  fact, 
that  the  infecting  organisms  are  the  comparatively  non- 
virulent  streptococci  of  the  salivary  and  intestinal  types. 
1  Practitioner,  May,  1908,  p.  715. 


THE  STREPTOCOCCUS  159 

Wilson1  examined  the  streptococci  isolated  from  five 
cases  of  streptococcal  meningitis.  Two  were  not  fully 
studied  owing  to  death  of  the  cultures — of  these,  one  was 
probably  pneumococcus  ;  the  other  was  not  'fsecalis,'  but 
possibly  '  pyogenes  longus.'  The  other  three  appeared 
to  belong  to  the  '  faecalis  '  variety. 


STREPTOCOCCAL  SEPTICAEMIA  AND  PYAEMIA. 

Several  cases  have  now  been  recorded  in  which  vaccine 
therapy  by  means  of  an  autogenous  vaccine  has  been 
resorted  to  in  this  variety  of  systemic  infection.  The 
first  case  was  described  by  Sir  James  Barr  before  the 
Liverpool  Medical  Institute  on  May  3,  1906,  the  treat- 
ment having  been  conducted  by  Captain  Douglas.  It 
was  a  very  severe  case,  rigors  occurring  every  twenty- 
four  hours  or  oftener,  when  the  temperature  mounted  to 
104°  or  105°  F.,  and  was  followed  by  profuse  sweating. 
There  was  an  attack  of  pleurisy  with  pleuro-pericardial 
friction,  but  without  marked  effusion.  All  the  various 
brands  of  anti-streptococcal  serum  had  been  tried  without 
much  benefit. 

Douglas  isolated  the  streptococcus  from  the  patient's 
blood,  and  a  vaccine  was  made.  The  index  was  estimated 
twice  daily,  and  injections  given  of  5,000,000  to  12,000,000 
cocci  at  each  fall  of  the  index. 

The  patient  made  an  excellent  recovery,  and,  except 
for  the  effects  of  phlebitis  in  the  left  lower  limb,  was  soon 
quite  well. 

Sutcliffe  and  Bayly 2  have  described  a  case  of  strepto- 
coccal septicaemia  in  a  boy  of  fourteen,  who  had  been 

1  Lancet,  December  28,  1907,  p.  1816. 

2  Ibid.,  August  10,  1907,  p.  367. 


160  VACCIXE  THERAPY 

operated  on  for  discharging  tubercular  glands,  which  was 
successfully  treated  with  a  streptococcal  vaccine.  Pus 
was  found  along  the  track  of  the  right  deep  femoral  vein, 
and  there  was  threatened  formation  in  a  similar  situation 
in  the  left  thigh.  The  cocci  were  isolated  from  the  blood, 
and  the  index  found  to  be  0-  66.  An  injection  of  10,000,000 
organisms  raised  the  index  to  Mo  by  the  folio  whig  day. 
In  the  course  of  forty -five  days  ten  injections,  varying  in 
amount  between  10,000,000  and  50,000,000  organisms, 
were  given.  Reduction  of  temperature,  elevation  of  the 
index,  and  general  improvement  in  the  patient's  condition 
ensued  after  each  injection,  and  complete  recovery  was  the 
ultimate  result.  Upon  two  occasions,  when  manipulation 
of  the  limb  was  performed,  considerable  depression  of  the 
index,  due  to  auto-inoculation,  was  observed  the  next  day. 

Turton  (loc.  cit.)  has  had  experience  of  three  cases. 

The  first  had  received  a  scratch  from  a  dirty  wire, 
there  was  oedema  and  redness  of  the  hand  and  arm.  and 
great  prostration  with  a  temperature  of  102°  F.  Injec- 
tions were  given  upon  the  third,  fifth,  eighth,  and  twelfth 
days  after  infection,  and  an  excellent  recovery  ensued. 

Case  number  two,  also  of  septicaemia,  had  a  favourable 
issue  after  four  injections  spread  over  seven  days. 

The  third  was  one  of  puerperal  septicaemia,  which 
seemed  hopeless  from  the  first.  Two  injections  on  the 
ninth  and  eleventh  days  after  parturition  seemed  to 
produce  no  good  result. 

Crowe  and  Wynn1  give  the  following  interesting  account 
of  a  case  of  puerperal  septicaemia  due  to  mixed  infection 
by  streptococcus  and  Bacillus  coli  communis,  and  therefore 
of  bad  prognosis.  Upon  the  ninth  day  after  labour  the 
temperature  rose  to  99-6°  F.,  and  clots  came  away  ;  on 
1  British  Medical  Journal,  August  8,  1908,  p.  303. 


THE  STREPTOCOCCUS  161 

the  fifteenth,  sixteenth,  and  seventeenth  days  the  tem- 
perature rose  to  100-4°  F.,  and  upon  the  eighteenth  to 
101°  F.,  when  Streptococcus  pyogenes  longus  and  Bacillus 
coll  communis  were  isolated.  Upon  the  eighteenth, 
twentieth,  twenty-first,  twenty-second,  and  twenty-fifth 
days  10  c.c.  of  antistreptococcal  serum  were  given  without 
any  good  result.  On  the  twentieth  day  the  index  to 
Streptococcus  pyogenes  =•  0-65.  Upon  the  twenty-fifth 
day  70,000,000  of  Bacillus  coli  communis  and  10,000,000 
of  streptococcus  of  autogenous  vaccines  were  given.  In 
the  evening  the  temperature  rose  to  102°  F.,  but  on  the 
third  morning  it  fell  to  normal,  the  indices  being  then  to 
Bacillus  coli  communis  T58,  to  streptococcus  T72.  The 
temperature  remained  normal  for  four  days,  then  rose  to 
100°  F.  This  was  recognized  as  being  due  to  two  carious 
teeth,  with  abcesses  at  their  roots.  These  were  extracted, 
and  recovery  proceeded  uninterruptedly. 

Wright l  relates  his  experiences  in  six  cases  of  strepto- 
coccal  septicaemia  (one  of  these  being  the  case  of  Barr 
and  Douglas,  already  described).  Of  these,  two  cases 
were  cured,  having  made  very  satisfactory  immunizing 
responses  ;  another  made  a  very  good  response,  but  died 
from  cardiac  complications  four  days  after  defervescence. 
Three  cases  died  without  making  any  immunizing  response 
to  the  inoculations,  despite  the  use  of  doses  varying 
greatly  in  magnitude. 

Results  such  as  those  recorded  above,  in  a  complaint 
of  such  grave  prognosis  as  streptococcal  septic semia,  can 
only  be  described  as  highly  satisfactory.  Control  of  the  in- 
oculations by  means  of  the  opsonic  index  is  highly 
desirable,  and  failure  to  secure  an  immunizing  response 
indicates  extreme  gravity  of  the  case. 

1  Lancet,  August  24,  1907. 

11 


162  VACCINE  THEEAPY 

Should  it  be  impossible  to  make  determinations  of  the 
index,  the  temperature-chart  and  clinical  condition  of  the 
patient  must  be  taken  as  the  guide  for  repetition  or 
increase  of  the  initial  dose  of  5,000,000  to  10,000,000. 

In  erysipelas,  empyema  (of  which  55  per  cent,  in 
adults  and  15  per  cent,  hi  children  Netter  has  shown  to 
be  due  to  streptococci),  secondary  joint  infections, 
dacryocystitis,  ulcers,  and  infected  wounds  and  endo- 
metritis,  the  Streptococcus  pyogenes  longus  is,  as  a  rule, 
the  variety  present.  Initial  doses  of  25,000,000  to  50,000,000 
may  safely  be  employed,  and  a  completely  satisfactory 
result  may  be  anticipated. 

ERYSIPELAS. 

Schorer1  studied  the  index  in  erysipelas,  and  the  effects 
of  therapeutic  inoculation  by  vaccines  and,  came  to  the 
following  conclusions  : 

The  onset  of  an  attack  causes  rise  of  index,  which  attains 
a  maximum  about  the  third  day,  and  then  gradually  falls. 

No  constant  change  in  index  occurs  at  the  time  of 
desquamation,  and  only  half  the  patients  discharged  as 
cured  have  a  higher  index  on  discharge  than  they  had  on 
admission. 

Injections  of  25,000,000  millions  cause  a  rise  of  index 
after  twenty-four  hours  without  any  preceding  negative 
phase.  Next  day  there  is  a  slight  fall,  but  a  raised  index 
is  maintained  for  about  seven  days.  With  a  dose  of 
50,000,000  the  rise  is  delayed  till  the  second  day. 

Inoculation  does  not  prevent  migration  or  recurrence, 
but  seems  to  shorten  the  duration  of  an  attack  by  about 
three  days. 

1  American  Journal  of  Medical  Science,  November,  1907,  p.  728. 


THE  STREPTOCOCCUS  163 

The  index  is  so  variable  that  it  is  of  no  use  as  an  in- 
dication of  the  severity  of  the  disease,  nor  is  it  of  value 
in  prognosis.  No  relation  was  observed  between  eleva- 
tion of  index  and  improvement  of  the  patient  as  the  effect 
of  injection.  Other  observers  have  obtained  much  more 
favourable  results,  and  a  case  by  Butler  Harris l  may  be 
specially  mentioned. 

From  a  case  of  severe  facial  erysipelas  an  autogenous 
vaccine  was  prepared  and  administered  upon  the  sixth 
day  when  the  temperature  was  105-4°  F.,  the  pulse  140, 
respiration  45,  and  the  patient  in  imminent  peril.  Re- 
covery resulted  by  crisis,  the  temperature  dropping  to 
98-8°  F.  fourteen  hours  after  inoculation. 

Wynn2  also  records  the  following  two  cases.  The  first, 
a  medical  man,  infected  his  finger  at  a  post-mortem  upon 
a  case  of  ulcerative  endocarditis.  The  infection  quickly 
spread  from  the  finger  to  the  axillary  glands  and  sub- 
cutaneous tissue  of  the  arm.  Severe  erysipelas  extended 
all  over  the  trunk  and  down  the  thighs,  and  the  patient 
became  dangerously  ill.  From  the  Streptococcus  longus 
isolated  a  vaccine  was  prepared.  The  opsonic  index  rose 
considerably  after  the  first  inoculation,  and  other  inocula- 
tions were  given,  when  daily  estimations  showed  the  index 
to  be  falling.  Good  response  followed  each  administra- 
tion. Prior  to  the  first  injection,  which  was  given  upon 
the  sixteenth  day,  the  temperature  had  showed  daily  rises 
to  102°  and  103°  F.,  and  on  the  thirteenth  day  to  105°  F. 
Subsequent  inoculations  were  given  on  the  eighteenth, 
twenty-first,  and  twenty-seventh  days.  Upon  the  twenty 
fourth  day  the  temperature  fell  to  normal,  and  the  patient 
made  a  good  recovery. 

1  Practitioner,  May,  1908,  p.  647. 

2  Birmingham  Medical  Review,  June,  1908 

11—2 


164  VACCINE  THERAPY 

The  second  case  was  one  of  severe  facial  erysipelas. 
The  temperature  showed  daily  rises  to  104°  F.,  and  once 
to  106°  F.,  with  remissions  to  100°  and  101°  F.  Inocula- 
tions of  10,000,000  were  given  on  the  third,  fifth,  tenth, 
thirteenth,  and  fourteenth  days  of  the  disease.  The 
temperature  dropped  by  crisis  on  the  day  following  the 
last  inoculation. 

RHEUMATISM  AND  CHOREA. 

Poynton  and  Paine  have  described  a  form  of  strepto- 
coccus as  being  the  probable  causative  agent  in  acute 
rheumatism.  It  exhibits  no  definite  distinctive  reac- 
tions. It  is  a  very  small  diplococcus,  growing  best  in  a 
mixture  of  equal  parts  of  milk  and  broth.  It  has  strong 
acid-forming  tendencies,  fermenting  glucose,  Isevulose, 
galactose,  maltose,  arabinose,  dextrin,  saccharose,  lactose, 
salicin,  and  mannite,  but  not  inulin,  dulcite,  or  sorbite.  It 
turns  milk  acid,  but  does  not  as  a  rule  form  a  clot.  It  forms 
acid  in  bile  salt  lactose  broth,  precipitating  the  litmus  and 
bile  salts.  When  grown  in  broth,  it  forms  considerable 
quantities  of  formic  acid  (Ainley  Walker)  ;  if  the  broth 
be  then  filtered  through  a  porous  porcelain  candle,  the 
Streptococcus  rheumaticus  will  fail  to  grow  in  the  filtrate, 
while  other  forms  of  streptococcus  will  grow  well.  The 
identity  of  this  organism  is  still,  however,  disputed. 

THE  INDEX  TO  '  STREPTOCOCCUS  RHEUMATICUS  '  IN 
ACUTE  RHEUMATISM  AND  CHOREA. 

Fordyce  l  observed  the  index  in  one  case  of  acute  rheu- 
matism with  pyrexia,  painful,  and  swollen  joints,  acute 
pericarditis  and  albuminuria.     Two  days  after  admission 
1  '  International  Clinics '  (eighteenth  series),  vol.  L,  p.  40. 


THE  STREPTOCOCCUS  165 

the  index  =0-59.  During  this  day  the  fever  and  the 
physical  signs  of  pericarditis  subsided.  Next  day  the 
patient  was  markedly  better  and  the  index  =  Tl  ;  for  the 
heated  serum  it  was  0-45  as  compared  with  0-1  for  a 
heated  normal  serum.  The  patient  steadily  improved, 
and  six  days  after  admission  the  index  =  1*3. 

In  ten  cases  of  chorea  he  found  the  index,  as  a  rule, 
low  upon  admission,  rising  later  as  the  general  health 
improved. 

The  lowest  index  found  =0-6,  the  highest  1-8.  Upon 
several  occasions  the  index  was  normal,  and  all  such 
indices  occurred  when  improvement  in  the  clinical  symp- 
toms was  taking  place,  and  upon  more  than  one  occasion 
was  an  intermediate  step  from  a  low  to  a  high  index. 

STREPTOCOCCI  IN  SCARLET  FEVER. 

The  view  has  steadily  grown  in  favour  of  late  that  strep- 
tococci are  intimately  connected,  at  all  events  with  the 
complications  of  scarlet  fever,  if  not  with  the  pathogenesis 
of  the  fever  itself.  Thus,  in  over  70  per  cent,  of  cases 
with  albuminuria,  streptococci  are  copiously  voided  in  the 
urine,  and  in  about  15  per  cent,  of  cases  without  albu- 
minuria. Bearing  this  in  mind,  Banks l  has  studied  the 
variations  in  the  opsonic  index  of  the  blood  to  strepto- 
cocci as  the  disease  progressed.  He  found  that  in  cases 
running  a  fairly  normal  course  the  opsonic  power  towards 
streptococci  varies  in  a  pretty  definite  and  constant  way. 
It  is  decreased  during  the  early  febrile  period,  and  rises 
to  normal  or  above  normal  during  the  defervescence  and 
general  decline  of  symptoms.  It  falls  during  the  second 
and  third  weeks,  and  even  in  uncomplicated  cases  the 

1  Journal  of  Pathology  and  Bacteriology,  October,  1907,  p.  113. 


166  VACCIXE  THERAPY 

index  may  be  comparatively  low.  There  is  an  increase 
to  normal  or  over  during  the  fourth  and  fifth  weeks.  In 
fatal  cases  with  severe  angina  the  opsonic  power  is 
markedly  subnormal.  Complications  alter  the  usual 
curve,  causing  both  absolute  and  relative  differences. 
Thus,  the  opsonic  power  is  decreased  at  the  onset  and 
during  the  earlier  period  of  albuminuria  and  secondary 
adenitis  ;  as  convalescence  is  established  the  index  rises. 
The  opsonic  values  do  not  furnish  many  data  for  prog- 
nosis, but,  in  general,  a  persistent  low  index  during 
nephritis  or  other  serious  complication  is  an  unfavourable 
sign. 

The  author,  therefore,  thought  it  worth  an  effort  to 
determine  whether  the  course  of  scarlet  fever  could  be 
favourably  influenced  by  the  administration  of  a  vaccine 
prepared  from  the  streptococci  isolated  from  the  throats 
of  scarlet  fever  patients.  From  the  throats  of  each  of 
twelve  such  cases  the  Streptococcus  '  conglomeratus,' 
both  of  the  small  and  large  types,  was  recovered,  and 
with  great  difficulty  a  mixed  vaccine  was  prepared.  The 
effect  of  this  was  then  tested,  in  conjunction  with  Dr. 
Goodall,  in  six  cases  of  uncomplicated  scarlet  fever,  but 
apparently  without  producing  the  slightest  good  effect, 
doses  varying  from  10,000,000  to  50,000,000  were  em- 
ployed. This  result,  although  discouraging,  is,  of  course, 
not  conclusive,  and  it  is  quite  possible  that  good  may  be 
effected  in  cases  complicated  by  angina,  adenitis,  and 
nephritis,  as  there  is  little  doubt  of  the  streptococcal 
nature  of  these  complications. 


CHAPTER  IX 

THE  PNEUMOCOCCUS 

THE  pneumococcus  causes  a  great  variety  of  suppurative 
conditions,  among  which  are  Pneumonia,  Pleurisy,  Peri- 
carditis, Endocarditis,  Empyema — both  pulmonary  (ac- 
cording to  Netter,  15  per  cent,  of  adult  secondary  cases 
and  65  to  90  per  cent,  of  all  cases  in  children)  and  of  the 
accessory  air  sinuses — Peritonitis,  Otitis,  Meningitis,  Con- 
junctivitis, Arthritis,  Periostitis,  Nephritis  and  Perine- 
phritis,  Metritis  and  Pyosalpinx,  Abscesses,  and  Pyaemia. 
It  is  also  the  cause  of  chronic  Ulcus  Serpens  Cornese. 

PNEUMONIA. 

MacDonald1  studied  the  index  in  eight  cases  of  pneu- 
monia, and  found  that  while  the  temperature  is  rising 
and  during  the  fastigium  the  opsonic  index  is  below 
normal,  whereas  at  the  onset  of  the  crisis  there  is  a  sudden 
rise,  even  as  high  as  1-6. 

Subsequent  observations  have  shown  that  in  very 
severe  cases  failure  of  the  index  to  rise  in  this  manner  at 
the  crisis  is  a  matter  of  very  grave  importance,  and  that 
such  cases  usually  die. 

Recent  attempts  have  been  made  in  America  to  treat 
pneumonia  as  a  routine  by  injection  of  a  vaccine,  and 
considerable  success  has  been  claimed.  The  temperature 

1  Pathological  Society,  London,  January  17,  1905. 
167 


168  VACCINE  THERAPY 

is  said  to  fall  several  degrees  within  twenty-four  hours  ; 
the  crisis  is  precipitated  within  three  or  four  days,  and  the 
convalescence  is  rapid  and  complete.  The  whole  duration 
of  the  disease  when  so  treated  is  claimed  to  lie  within  a 
fortnight. 

Butler  Harris l  refers  to  four  cases  of  pneumonia 
which  failed  to  immunize  themselves,  and  responded  at 
once  to  the  introduction  of  a  vaccine  made  from  the 
patient's  own  pneumococcus — details  of  the  cases  are  not 
given.  Favourable  experiences  of  the  routine  injection 
by  25,000,000  organisms  of  cases  of  acute  pneumonia  have 
been  communicated  to  me  privately,  but  have  not  as  yet 
been  published. 

Unresolved  pneumonia  would  appear  to  be  particularly 
suitable  for  vaccine  therapy. 

Coleman  recorded  before  the  Royal  Academy  of  Medi- 
cine, Ireland,  on  March  2,  1906,  such  a  case  treated  by 
inoculation  of  pneumococcal  vaccine  with  very  satis- 
factory results. 

On  the  thirty-eighth  day  of  attack  the  pneumococcic 
index  was  0-6;  46,500,000  cocci  were  therefore  given. 
There  was  no  disturbance,  local  or  general.  Next  day  the 
index  was  0'69,  and  the  physical  signs  were  those  of 
pneumonia  of  five  or  six  days'  standing. 

6  days  after  injection  the  index  =  1- 17,  and  the  patient 

was  much  better. 
10  days  after  injection  the  index  =  0-89,   and  46,500,000 

were  again  given. 
3  days  after  second  injection  the  index  =  1-13. 

Eleven  days  after  the  second  injection  the  patient  was 
in  excellent  health,  and  for  six  weeks  subsequently  the 
index  was  observed  to  be  slightly  over  normal. 
1  Practitioner,  May,  1908,  p.  647. 


THE  PNEUMOCOCCUS  169 

Briscoe  and  Williams1  subjected  four  such  cases, 
which  were  not  improving  under  ordinary  treatment,  to 
vaccine  therapy.  Cultures  were  made  from  the  patients' 
own  organisms,  and  the  guidance  of  the  opsonic  index 
was  utilized. 

Case  1  was  in  a  child  aged  one  and  a  half  years.  A  month 
after  admission  a  consolidation  at  the  right  base  was  still 
unresolved.  The  index  being  0-  9,  an  injection  of  20,000,000 
cocci  was  given.  A  slight  rise  of  temperature  resulted, 
and  the  child  was  not  so  well  for  eighteen  hours.  He  then 
began  to  improve  in  weight  and  general  condition. 

2  days  after  the  first  injection  the  index  =  1'2. 

4  days  after  the  first  injection  there  were  only  a  few  crepi- 

tations and  slight  bronchial  breathing. 

5  days  after  the  first  injection  the  index  =  1-3. 

6  days  after  the  first  injection  there  were  crepitations, 

but  no  bronchial  breathing. 
9  days  after  the  first  injection  the  index  =  1-2. 
11  days  after  the  first  injection  10,000,000  cocci  were  given 

without  any  ill  effect,  and  next  day  index  =  1-4. 
2  days  after  the  second  injection  crepitations  were  audible 

only  at  lower  and  posterior  aspect  of  the  lobe. 
5  days  after  the  second  injection  10,000,000  cocci  were 

given,  and  next  day  the  chest  was  clear. 

Case  2  was  in  a  child  aged  one  year  and  nine  months,  and 
was  readmitted  two  months  after  having  been  admitted 
for  right  basal  and  later  apical  consolidation.  Turbid 
fluid  was  found,  and  one  injection  of  20,000,000  given. 
The  child  steadily  got  worse,  and  died  in  a  few  days.  Post- 
mortem, loculated  septic  pericarditis  with  universal 
mediastinitis,  collapse  and  consolidation  of  the  right  lung 
was  found.  The  presence  of  the  old-standing  septic 
pericarditis  may  be  held  to  have  contra-indicated  vaccine 
therapy,  and  the  case  is  hardly  a  fair  one  upon  which  to 
base  any  conclusion. 

1  Practitioner,  May,  1908,  p.  675. 


170  VACCINE  THERAPY 

Case  3  was  in  a  child  of  two,  in  whom  the  temperature 
remained  intermittent  after  drainage  of  an  empyema. 
Two  injections,  the  first  of  10,000,000,  the  second  of 
40,000,000,  eight  days  after  the  first,  were  given.  Measles, 
unfortunately,  complicated  the  case,  but  the  authors  state 
that  the  child's  general  condition  was  improved,  and  the 
temperature  slightly  reduced  as  a  result  of  the  inoculations. 

Case  4  was  one  of  right  basal  consolidation  with  a  history 
of  one  week  in  a  man  of  forty-four.  Although  the  tem- 
perature soon  fell  to  normal,  the  local  signs  failed  to  clear 
up.  Sixty  million  organisms  were  therefore  injected  on 
about  the  twenty-second  day,  and  again  thirteen  days 
later.  After  the  first  injection  the  moist  sounds  cleared 
up  entirely  in  the  next  three  days,  and  the  sputum 
diminished  two  days  after  the  second  injection.  There 
was  no  bronchial  breathing,  but  the  breath  sounds  were 
a  little  harsh.  His  general  and  mental  condition,  pre- 
viously bad,  improved  rapidly. 

The  authors'  conclusions  are  that  'in  these  more  or 
less  acute  cases  the  improvement  in  general  condition 
is  quite  a  marked  feature,  and  it  appears  to  be  an  impor- 
tant factor  hi  the  question  of  continuing  the  treatment. 
The  injection  produces  a  stimulating  effect,  and  the 
patients  always  seem  to  be  more  cheerful  afterwards.  An 
increase  of  weight  occurs  rapidly  in  the  case  of  children.' 

They  also  produced  decided  improvement  in  two  cases 
of  a  chronic  nature  in  adults,  the  history  in  each  dating 
back  ten  months.  Doses  of  50,000,000  and  100,000,000 
were  employed. 

In  empyemata  good  results  may  be  anticipated  when 
vaccine  therapy  is  directed  against  the  organisms  found 
to  be  present.  In  only  a  certain  percentage  are  pneu mo- 
cocci  alone  present  ;  in  some  cases  they  are  absent  alto- 


THE  PNEUMOCOCCUS  171 

gether  ;  in  most  there  is  a  mixed  infection  with  strepto- 
cocci, staphylococci,  Bacillus  pyocyaneus,  Bacillus  coli  com- 
munis,  etc.  ;  and  in  these  a  mixed  vaccine  will  have  to  be 
employed  in  conjunction  with  such  measures  as  surgical 
experience  indicates.  Improvement  may  be  slow,  and 
prolonged  treatment  necessary. 

A  number  of  cases  have  now  been  reported  in  which 
the  pneumococcus  has  been  found  to  be  responsible  for 
metritis  and  pyosalpinx,  and  in  a  few  instances  for  a 
resultant  peritonitis  and  systemic  infection.  The  possi- 
bility of  this  might  well  be  borne  in  mind  by  obstetricians 
and  abdominal  surgeons,  and  recourse  made  to  vaccine 
therapy.  Jowers x  records  such  a  case  in  a  girl  of  fourteen, 
in  whom  a  diagnosis  of  general  peritonitis,  secondary, 
probably,  to  perforated  appendix,  was  made.  At  operation 
the  appendix  was  found  to  be  normal,  but  the  right 
Fallopian  tube  distended,  the  ovary  swollen  and  adherent 
to  the  pelvic  wall.  The  abdomen  contained  colourless 
pus.  The  pneumococcus  was  isolated  in  pure  culture 
and  a  vaccine  made. 

Upon  the  eighth  day  after  operation  50,000,000  cocci 
were  given  ;  upon  the  tenth  day  60,000,000,  and  upon  the 
thirteenth  day  after  operation  200,000,000  were  given 
without  the  control  of  the  opsonic  index. 

The  temperature  only  came  to  normal  after  five  weeks, 
the  pulse  all  this  time  being  high.  The  child  then  made 
a  good  recovery.  The  impression  conveyed  from  the 
published  account  is  that,  if  the  vaccine  therapy  had 
been  controlled  by  index  determination  and  persisted  in, 
a  more  speedy  result  would  have  been  obtained. 

For  Ulcus  serpens  cornea  and  Pneumococcal  conjunctivitis, 
see  Chapter  XIV. 

1  Practitioner,  September,  1908. 


CHAPTER  X 
THE  GONOCOCCUS 

THE  chief  conditions  set  up  by  this  organism  are  Ure- 
thritis,  Periurethritis,  Prostatitis,  Vesiculitis,  Cystitis, 
Epididymitis  and  Orchitis,  Endometritis,  Salpingitis, 
Peritonitis,  Conjunctivitis,  Endocarditis,  Arthritis,  and 
even  Pleurisy  and  Septicaemia.  In  these  connections  a 
very  wide  field  of  utility  is  afforded,  both  in  the  diagnosis 
and  treatment. 


THE  OPSONIC  INDEX  IN  GONOCOCCAL  INFECTIONS,  AND 
ITS  UTILITY  IN  DIAGNOSIS  AND  TREATMENT. 

In  acute  gonorrhceal  infections  of  the  urethra  the  index, 
as  a  rule,  first  falls  for  a  few  days  to  0-6  or  0*7  ;  it  may 
then  either  rise  steadily  to  1'3  or  1'6,  such  cases  usually 
doing  well  under  routine  treatment,  or  it  may  continue 
subnormal,  when  they  usually  pass  on  into  a  chronic 
intractable  gleet. 

In  chronic  cases  the  index  is  usually  low,  even  0*3  ; 
it  is,  however,  sometimes  normal  or  above  normal,  but 
in  these  cases  cocci,  as  a  rule,  are  to  be  found  copiously 
in  the  secretions  from  suppurating  Littre's  glands  or 
sinuses,  which  may  continue  thus  to  discharge  at  intervals 
for  many  years. 

172 


THE  GONOCOCCUS  173 

In  acute  gonorrhceal  conjunctivitis  in  adults  the  index 
may  be  as  high  as  2,  or  even  2-5. 

Every  genito-urinary  surgeon  and  obstetrician  is 
familiar  with  the  great  difficulty  of  deciding  whether  an 
old  gonorrhceal  infection  has  disappeared,  or  of  arriving 
at  a  diagnosis  in  cases  where  a  history  of  an  acute  attack 
is  not  obtainable.  In  the  male  it  is  no  very  uncommon 
thing  for  a  discharge  to  persist  even  for  ten  years  after 
an  attack  of  acute  gonorrhoea.  Stained  films  do  not 
reveal  the  presence  of  any  gonococci,  but  only  of  strepto- 
cocci, staphylococci,  the  bacillus  of  Friedlander,  the 
Micrococcus  catarrhalis,  and  other  +  and  —  Gram 
organisms.  The  difficulty  of  advising  as  to  the  safety  or 
otherwise  of  marriage  in  these  cases  is  considerable.  In 
deciding  whether  there  are  any  latent  gonococci  en- 
capsuled  in  the  numerous  urethral  crypts  and  diverticula 
I  have  found  the  opsonic  index  of  the  utmost  assistance. 
Brief  references  to  a  few  cases  will  illustrate  this. 

Case  1  had  a  chronic  discharge  for  ten  years.  No  gono- 
cocci could  be  found  in  films,  but  the  bacillus  of  Fried- 
lander  was  present  in  vast  numbers  in  a  state  of  purity. 

The  gonococcal  index  was  I'l,  that  towards  the  bacillus 
of  Friedlander  0-6.  Non-gonococcal  infection  was  diag- 
nosed, and  treatment  by  means  of  a  vaccine  prepared 
from  the  pneumobacillus  carried  out  with  complete 
success. 

Case  2  was  one  of  twelve  years'  standing,  which  had 
proved  obdurate  to  every  form  of  treatment.  No  gono- 
cocci could  be  detected  in  smears  or  cultures,  and  the 
index  was  1-2.  The  patient  desired  a  course  of  injections 
with  gonococcal  vaccine,  and  five  were  accordingly  given, 
but,  as  anticipated,  without  influencing  the  discharge. 
A  combined  vaccine  was  then  prepared  from  the  urethral 


174 


VACCINE  THERAPY 


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THE  GONOCOCCUS  175 

organisms  present  ;  two  injections  sufficed  to  reduce  these 
greatly  in  numbers  and  variety,  and  a  fresh  vaccine  was 
then  made. 

Two  injections  with  this  resulted  in  great  diminution 
of  the  discharge,  which  contained  only  epithelial  and 
lymphoid  cells  and  few  organisms,  which  were  contained 
within  the  epithelial  cells,  and  proved  very  difficult  to 
cultivate.  Subsequent  irrigation  for  a  few  days  with 
weak  solutions  of  perchloride  of  mercury  completely 
cured  the  discharge. 

In  these  two  cases,  then,  the  gonococcal  index  was 
normal,  and  the  diagnosis  of  non-gonococcal  infection 
was  amply  confirmed  by  the  results  of  treatment. 

Cases  3  and  4  were  each  of  ten  years'  standing,  and  had 
undergone  the  most  expert  surgical  treatment,  both  in 
England  and  upon  the  Continent,  but  without  avail  ; 
exacerbations  appeared  from  time  to  time  without  any 
obvious  cause.  In  Case  3  no  gonococci  were  to  be  found, 
in  Case  4  only  at  intervals.  The  indices  were  found 
to  be  0-4  and  0-5  respectively  ;  gonococcal  infection  was 
therefore  diagnosed,  and  opsonic  treatment  advised,  with 
complete  success,  two  injections  sufficing  in  the  instance 
of  Case  4. 

Case  5  was  sent  me  by  Mr.  Wyndham  Powell,  and  is 
peculiarly  interesting.  The  attack  was  a  first  one. 
Intercourse,  which  had  taken  place  seven  days  previously, 
was  followed  by  discharge  three  days  later.  The  patient 
at  once  saw  Professor  Janet,  who  diagnosed  a  simple 
non-gonococcal  urethritis.  Mr.  Powell  was  of  the  same 
opinion,  but,  owing  to  the  extensive  involvement  of 
Littre's  glands,  desired  confirmation.  Cultures  of  the 
secretion  gave  pure  Staphylococcus  albus,  even  after 
thorough  irrigation  of  the  urethra.  The  gonococcal  index 


176  VACCINE  THERAPY 

was  found  to  be  0-9.  The  staphylococcal  index  was 
found  to  be  0*7.  Confirmation  was  thus  afforded  of  the 
non-gonococcal  nature  of  the  infection,  which  was  con- 
sidered to  be  staphylococcal  in  nature.  A  vaccine  was 
made,  and  an  injection  of  150,000,000  organisms  given. 
A  second  similar  injection  was  given  three  weeks  later,  and 
the  patient  appeared  to  be  improving.  Unfortunately,  he 
left  England  a  fortnight  later,  and  the  success  or  otherwise 
of  the  treatment  could  not  be  determined. 

Case  6  was  a  case  of  old  gonococcal  infection  in  the 
female,  the  discharge  recurring  at  practically  every  men- 
strual period.  Advantage  was  taken  of  the  fact  that 
during  a  period  the  index  towards  any  infecting  organism 
falls  considerably  :  two  days  prior  to  menstruation  the 
index  was  found  to  be  0-7  ;  upon  the  fourth  day  it  was 
only  0-3.  The  diagnosis  of  gonococcal  infection  was 
therefore  made,  and  amply  confirmed  by  the  results  of 
opsonic  treatment.  In  three  months  the  woman  felt  a 
totally  different  person,  and  had  gamed  a  stone  in  weight. 

The  evidence  afforded  by  these  and  numerous  other 
cases  of  chronic  urethritis  serves  to  indicate  that  in 
many  instances,  though  the  gonococcal  infection  has  died 
out,  the  gonococcal  toxins  and  antiseptics  faultily  applied 
have  resulted  in  a  weakened  mucous  surface,  upon  which 
numerous  pathogenic  organisms,  usually  of  low  virulence, 
are  enabled  to  flourish  and  multiply.  These  prove  ex- 
tremely resistant  hi  many  instances  to  local  forms  of 
treatment,  but  sometimes  readily  respond  to  injections  of 
vaccines,  a  series  of  which  may,  however,  be  required. 
In  view  of  the  extreme  importance  of  eliminating  every 
chance  of  the  continuance  of  a  gonococcal  infection,  it  is 
good  practice  in  all  cases  where  the  index  is  on  the  border- 
line of  the  normal — i.e.,  0-8  or  1-2 — to  begin  the  treatment 


THE  GONOCOCCUS  177 

of  such  cases  with  injections  of  a  gonococoal  vaccine,  even 
though  no  gonococci  are  to  be  found  in  the  secretion.  A 
first  dose  of  75,000,000  organisms  is  best  given  ;  should 
this  produce  no  effect,  it  may  be  followed  by  a  second  of 
double  the  amount.  Should  only  slight  disturbance  of 
the  index  result,  the  non-gonococcal  nature  of  the  infec- 
tion may  be  considered  established,  and  treatment  then 
begun  with  a  combined  vaccine.  Such  treatment  can  do 
no  possible  harm,  and  may  prevent  a  gonococcal  case 
being  missed.  It  must,  however,  be  noted  that  even  per- 
sistent treatment  of  some  cases  of  chronic  urethritis  will 
fail  to  cure  entirely  the  discharge  and  threads  in  the  urine. 
The  patients  feel  better,  suffer  no  discomfort  and  put 
on  weight,  yet  a  small  bead  of  discharge  may  be  expressed 
in  the  morning.  Although  such  cases  may  safely  be  left 
in  such  a  condition,  none  having  retrogressed  within  my 
experience,  further  improvement  may  possibly  be 
secured  according  to  the  method  I  employed  in  two 
instances.  Both  were  very  old  chronic  cases,  one  of 
thirteen  years',  the  other  of  fifteen  years'  standing,  and 
both  when  they  came  under  my  care  had  profuse  discharge 
which  worried  them  greatly.  Every  conceivable  method 
of  surgical  treatment  had  been  employed  upon  them. 
After  a  preliminary  course  of  gonococcal  vaccine,  a  whole 
series  of  vaccines  prepared  from  the  urethral  organisms 
was  employed  in  turn.  Both  cases  improved  very 
greatly,  yet  each  morning  it  was  possible  to  express  a 
bead  of  discharge  containing  great  numbers  of  organisms, 
both  staining  and  failing  to  stain  by  Gram's  method. 

As  a  last  resort  I  decided  to  inject  cultures  of  living 
lactic  acid  bacteria  into  the  urethra,  with  the  aid  of  an 
ordinary  syringe,  twice  daily  for  a  week.  The  first  day 
there  was  slightly  increased  discharge  and  considerable 

12 


178  VACCINE  THERAPY 

itching  ;  subsequently  the  injections  resulted  in  less  dis- 
charge, but  the  irritation  continued.  At  the  end  of  a 
week  of  this  treatment  the  urethra  was  thoroughly  flushed 
out  with  weak  potassium  permanganate  solution  night 
and  morning.  Next  day  the  irritation  had  disappeared, 
and  smears  were  obtained  with  great  difficulty ;  no 
organisms  could  be  detected,  and  cultures  were  also 
sterile.  Both  patients  have  remained  well.1 

I  have  of  late  made  a  routine  practice  of  giving  every 
case  of  acute  gonorrhoea  one  or  two  injections  of  vaccine, 
the  first  being  administered  as  soon  as  the  acuter  symp- 
toms have  begun  to  subside,  and  the  thick  discharge  to 
dimmish.  Convalescence  has  been  complete  in  two  or 
three  weeks,  and  secondary  complications  and  backward 
extension  have  failed  to  appear  in  any  of  the  series. 
This  procedure  can  be  warmly  recommended. 


GONOCOCCAL  ARTHRITIS. 

Cole  and  Meakins2  record  their  observations  upon 
fifteen  cases. 

They  found  the  index  subnormal,  varying  between 
0-  2  and  0- 7.  An  initial  dose  of  200,000,000  to  300,000,000 
was  found  to  raise  the  index  above  normal  in  each  case, 
the  maximum  height  being  attained  between  the  second 
and  seventh  day,  while  a  return  to  normal  occurred  on 
about  the  tenth  day. 

The  injections  were  carried  out  under  the  guidance  of 
the  index  (as  estimated  upon  counts  of  fifty  cells),  and 

1  The  fluid  employed  for  injection  can  be  obtained  from  W.  H. 
Martindale  under  the  name   of   '  Trilactine    liquid,    special,  for   in- 
jection.' 

2  Bulletin  of  Johns  Hopkins  Hospital,  June  and  July,  1907,  p.  223. 


THE  GONOCOCCUS  179 

gradually  raised  till  1,000,000,000  were  administered. 
General  constitutional  disturbance  was  very  rare,  and  in 
only  one  case  severe.  The  interval  between  injection  was 
seven  to  ten  days.  They  found  that  any  coincident 
urethritis  or  prostatitis  was  much  less  amenable  to  the 
vaccine  therapy  than  the  arthritic  condition.  In  regard 
to  this  latter  they  concluded  that  the  results  in  the 
chronic  cases  were  more  marked  than  in  the  acute  ;  cases 
which  had  progressed  but  very  slowly  under  other  methods 
of  treatment  showed  much  more  rapid  improvement. 
Their  opinion  was  that  the  vaccine  treatment  had  been  of 
distinct  value,  a  conclusion  amply  borne  out  by  the 
clinical  details  given. 

Irons 1  has  also  studied  40  cases  of  gonococcal  infection, 
31  being  arthritic.  In  15  of  the  cases  the  index  was 
systematically  studied,  and  found  initially  to  be  low, 
but  clinical  symptoms  were  used  as  the  guide  to  size 
and  interval  of  injections.  The  vaccines  used  were  hetero- 
logous,  and  univalent,  divalent,  or  trivalent,  little  ad- 
vantage being  noticed  from  the  use  of  a  polyvalent 
vaccine.  At  first  initial  doses  of  20,000,000  to  50,000,000 
were  employed,  but  in  later  cases  these  were  increased 
advantageously  to  100,000,000  and  even  1,000,000,000, 
the  intervals  between  injections  varying  from  three  to 
seven  days.  The  injection  of  500,000,000  dead  gonococci 
into  the  tissues  of  a  person  free  from  gonococcal  infection 
was  found  in  eight  cases  to  produce  practically  no  consti- 
tutional disturbance  ;  quite  otherwise  was  the  result  in 
infected  cases.  In  these,  within  twenty-four  hours,  and 
corresponding  to  the  negative  phase,  there  is  increased 
articular  pain,  tenderness,  rise  in  temperature,  and 
general  malaise,  so  that  the  suggestion  was  made  to  employ 

1  Archives  of  Internal  Medicine,  vol.  i.,  No.  4,  p.  433. 

12—2 


180  VACCINE  THERAPY 

this  reaction  as  a  diagnostic  in  cases  of  doubtful  gonococcal 
infection. 

Inasmuch  as  the  clinical  course  of  gonococcal  infections 
is  very  variable,  and  the  great  majority  of  arthritic  cases 
ultimately  recover  spontaneously,  Irons  is  particularly 
guarded  in  drawing  conclusions  from  the  results  of  his 
observations,  but  considers  that  in  certain  cases  of 
gonococcal  arthritis  recovery  can  be  hastened  by  vaccine 
therapy,  this  assistance  being  more  marked  in  subacute 
and  chronic  ambulatory  cases  than  in  acute  ones,  although 
in  several  such  cases  improvement  was  apparently  more 
rapid  immediately  following  an  injection  than  it  was 
before. 

GONORRHCEAL   VULVO-VAGINITIS    IN    CHILDREN. 

Butler  and  Long l  studied  the  effect  of  vaccine  therapy 
in  twelve  such  cases.  They  controlled  their  work  by 
means  of  index  determination,  and  reinjected  before  the 
index  fell  again  below  normal.  They  found  that  the 
dosage  could  only  be  determined  by  investigating  each 
individual  case,  either  a  too  small  or  a  too  large  dose 
resulting  in  little  or  no  response.  The  doses  varied  from 
1,000,000  to  50,000,000,  and  an  initial  one  of  5,000,000 
is  recommended. 

The  ages  of  the  twelve  cases  were  between  one  and  a 
half  and  twelve  years,  and  the  results  were  compared  with 
those  obtained  in  twelve  other  similar  cases  treated 
locally  with  potassium  permanganate  and  argyrol. 

In  four  of  the  twelve  cases  treated  with  vaccine  clinical 
evidences  of  gonorrhea  disappeared  in  from  ten  to 
twenty-one  days,  and  gonococci  could  not  be  found  in 
smears. 

1  Journal  of  American  Medical  Association,  March  7,  1908,  p.  744. 


THE  GONOCOCCUS  181 

In  five  cases  a  cessation  of  discharge  and  disappearance 
of  gonococci  from  the  smears  were  secured  after  several 
weeks  of  treatment,  a  change  from  a  univalent  to  a  poly- 
valent vaccine  being  found  beneficial. 

Of  the  remaining  three  cases,  in  two  the  discharge 
ceased,  but  recurred  after  treatment  was  stopped,  although 
ultimately  gonococci  disappeared  from  smears  ;  in  the 
last  case,  recurrence  was  followed  by  cure. 

Of  the  12  control  cases,  in  9  treated  respectively 
twenty -five,  twenty -six,  twenty -six,  twenty  -  seven, 
twenty-nine,  forty,  forty-nine,  sixty-three,  and  ninety-six 
days  cessation  of  discharge  was  not  secured,  while  in  the 
remaining  3,  under  treatment  respectively  thirty-one, 
thirty-two,  and  one  hundred  and  seventy-six  days,  a 
favourable  result  was  secured. 

Their  conclusion  is  that  vaccine  therapy  appears  to  be 
far  more  efficient,  and  at  the  same  time  scientifically  more 
tenable  than  local  antiseptic  treatment  in  these  cases. 

Despite  the  researches  of  Torrey,1  who,  from  a  study 
of  the  agglutinins  and  precipitins  in  anti-gonococcal  sera, 
came  to  the  conclusion  that  the  family  gonococcus  is 
heterogeneous  rather  than  homogeneous,  the  view  of  its 
being  a  definite  entity  is  usually  held.  Wherever  pos- 
sible, it  is  undoubtedly  best  to  prepare  a  vaccine  from 
the  patient's  own  organisms  ;  but  should  the  virulence  of 
these  have  been  reduced  by  antiseptic  treatment  or  by 
the  long  duration  of  the  infection,  it  is  decidedly  better 
to  employ  a  vaccine  made  from  a  strain  of  known  high 
virulence.  In  eye  cases  one  should  inject  immediately 
the  diagnosis  is  established,  without  waiting  to  determine 
the  index  or  prepare  a  vaccine.  The  index  in  all  eye 
infections,  acute  or  chronic,  due  to  whatever  organism, 
1  Journal  of  Medical  Research,  Boston,  May,  1907,  p.  329. 


182  VACCINE  THERAPY 

is,  as  a  rule,  exceptionally  high.  The  reason  for  this  is 
fairly  obvious.  The  circulation  of  that  part  is  poor,  the 
area  of  infection  small ;  consequently  the  toxins  formed 
are  absorbed  in  such  minute  quantities  that  they  act  like 
very  small  doses  of  vaccine,  and  tend  to  raise  the  index. 
If  other  areas  in  the  body  are  infected,  as  is  often  the  case 
in  tubercular  cases,  this  reasoning  does  not  apply,  and 
the  index  corresponds  to  the  nature  of  the  other  area  of 
infection.  That  the  already  high  index  so  often  fails  to 
effect  cure  in  these  cases  is  due  to  the  same  cause — poor 
blood-supply  and  poor  lymph  flow  ;  hence  in  such  cases 
high  index  is  no  contra-indication  to  injection. 

The  dosage  in  gonococcal  cases  requires  particular  atten- 
tion. Owing  possibly  to  the  powerful  toxins  formed  by 
this  organism,  the  initial  doses  employed  are  smaller  than 
in  the  case  of  most  other  organisms  :  50,000,000  organisms 
may  be  used  with  advantage  upon  the  first  occasion, 
100,000,000  being  employed  upon  the  second,  if  indi- 
cated by  the  index.  Subsequently  larger  doses  than 
500,000,000  are  not  often  required. 

As  regards  the  frequency  of  administration,  this  should 
always  be  controlled  by  determinations  of  the  index.  A 
negative  phase,  lasting  for  a  fortnight,  with  a  dose  of 
100,000,000  or  150,000,000  organisms,  is  by  no  means 
infrequent,  in  which  case  little  advantage  can  accrue 
from  fresh  injection  before  the  end  of  a  month. 

As  in  the  case  of  tubercle,  it  is  particularly  bad  practice 
to  inject  without  estimating  the  index  the  day  before  ; 
if  this  cannot  be  done,  it  is  better  to  err  on  the  side  of 
waiting  a  week  too  long  rather  than  on  that  of  injecting 
a  week  too  soon.  It  may,  however,  be  noted  that  occa- 
sionally the  result  of  a  first  injection  is  a  continued 
negative  phase  ;  the  index  drops  a  few  decimal  points, 


THE  GONOCOCCUS  183 

and  is  only  raised  by  a  second  injection  of  like  strength. 
Should,  however,  the  index  still  remain  depressed,  it  is 
best  to  wait  four  or  five  weeks,  and  begin  again  with 
reduced  dosage. 

Another  peculiarity  about  this  organism  is  the  marked 
improvement  of  clinical  features  which  occasionally 
results  during  the  negative  phase.  Increased  discharge 
often  occurs  during  the  first  two  or  three  days,  but  then 
rapidly  diminishes,  despite  the  continued  presence  of  the 
negative  phase.  Clinical  symptoms  are  therefore  a 
totally  unreliable  guide  as  to  the  appropriate  time  for 
fresh  injections. 


CHAPTER  XI 

THE    OPSONIC    TREATMENT    OF    CATARRH,    NASAL    AND 
TRACHEAL,  AND  OF  THE  ACCESSORY  AIR  SINUSES 

DURING  the  last  four  years  the  author  has  been  working 
continuously  upon  this  question.  A  paper  is  appearing 
upon  the  subject  in  the  Lancet  shortly,  but  some  of  its 
essential  features  may  here  be  given. 


THE  BACTERIOLOGY. 

1.  Of  Nasal  Catarrh. — Forty-two  cases  of  nasal  catarrh, 
acute  and  chronic,  were  examined  bacteriologically  and  the 
causative  organisms  determined,  with  the  following  results : 

The  bacillus  of  Friedlander  alone  in  8  cases . .  =  19'0  per  cent. 

The  Bacillus  influenzce  alone  in  1  case        . .  =   2'4  „ 

The  Bacillus  septus  alone  in  11  cases         . .  =26- 2  ,, 

The  Micrococcus  catarrhalis  alone  in  12  cases  =  28- 6  „ 
The  bacillus  of  Friedlander  +  Bacillus  septus 

in  3  cases    ..         ..         ..          ..  =   7*1  ,, 

The    bacillus    of    Friedlander  +  Micrococcus 

catarrhalis  in  2  cases          . .          . .  =   4'7  ,, 
The  Bacillus  septus  +  Micrococcus  catarrhalis 

in  4  cases               . .         . .         . .  =   9*7  „ 

No  definite  organism  isolated  in  1  case      . .  =   2*4  ,, 

Considering  the  acute  and  chronic  forms  separately, 
the  following  causal  relationship  was  determined  : 


Bacillus  of 

Bacillus 

Bacillus 

Micrococcus 

Friedlander. 

influetizce. 

septus. 

catarrhalis. 

Acute 

Yes 

Yes 

Yes 

Yes 

Subacute     .  . 
Chronic 

Yes 

Yes 

Rarely 
No 

Rarely 
No' 

Yes 

No 

184 


THE  OPSONIC  TREATMENT  OF  CATARRH     185 

It  would  thus  appear  that  the  only  common  cause  of 
non-suppurative  chronic  nasal  catarrh  is  the  bacillus  of 
Friedlander. 

2.  Of   Tracheal   Catarrh. — The   Bacillus   septus  would 
appear  never  to  set  up  this  condition  ;  the  bacillus  of 
Friedlander  very  exceptionally  ;  the  Bacillus  inftuenzce 
and  the  Micrococcus  catarrTialis  habitually. 

It  must,  however,  be  noted  that  the  latter  of  these  is 
frequently  present  in  perfectly  heathly  tracheas,  just  as 
in  certain  healthy  individuals  the  pneumococcus  is 
always  to  be  found  in  their  sputum.  A  catarrh  of  the 
trachea  set  up  by  the  Micrococcus  catarrhalis  soon,  more- 
over, becomes  secondarily  infected  with  other  organisms, 
just  as  does  a  catarrh  of  the  conjunctival  or  urethral 
mucous  membranes.  The  prime  factor  is,  however,  the 
Micrococcus  catarrhalis,  which  is  also,  I  believe,  the  prob- 
able cause  of  many  cases  of  bronchitis. 

3.  Of  the  Accessory  Air  Sinuses. — Lewis   and   Logan 
Turner  x  made  a  number  of  careful  bacteriological  exam- 
inations, both  in  the  cadaver  and  on  the  living  subject. 
A  great  variety  of  organisms  were  found,  chief  among 
which  were  the  staphylococcus,  streptococcus,  pneumo- 
coccus, and  bacillus  of  Friedlander.     Just  as  in  the  case 
of  the  lachrymal  duct  the  acute  infection  due  to  Koch- 
Weeks    bacillus,    the    Bacillus    lacunatus,    Bacillus    coli, 
staphylococcus,   or  gonococcus  becomes  secondarily  in- 
fected by  the  Streptococcus  pyogenes,  which  ultimately 
displaces  the  other  organisms  altogether,  and  maintains 
a  chronic  dacryocystitis,  so  I  believe  in  these  cases  the 
prime  infection  in  many  cases  to  be  due  to  an  attack  of 
acute  nasal  catarrh  due  to  the  Bacillus  influenzce,  bacillus 
of  Friedlander,  Bacillus  septus,  or  Micrococcus  catarrhalis, 

1  Edinburgh  Medical  Journal,  November,  1905. 


186  VACCIXE  THERAPY 

and  that  the  staphylococci,  streptococci,  and  pneumo- 
cocci  are  secondary  infections,  maintaining  a  chronic 
condition.  This  probably  affords  ample  explanation  of 
the  fact  that  chronic  nasal  catarrhs  with  sinusitis  fail  to 
give  entirely  satisfactory  results,  as  we  shall  see,  with 
vaccine  of  the  bacillus  of  Friedlander. 

THE  OPSONIC  TREATMENT  OP  ACUTE  CATARRH  OF  THE 
RESPIRATORY  PASSAGES. 

Distressing  as  is  the  stage  of  acute  discharge  hi  eas^s 
of  colds,  the  discomfort  is  slight  compared  with  that  of 
the  subacute  stage,   when  the  discharge  is  thick    and 
grumous  and  blocks  up  all  the  nasal  passages.     This  part 
of  an  attack  can,  I  have  found,  be  cut      wn  to  a  duration 
of  only  two  or  three  days  by  the  injection  of  a   suitable 
vaccine.     As  soon  as  the  patient  is  seen,   smears  and 
cultures  should  be  made  of  the  mucous  discharge  and  the 
infecting  organism  ascertained.     Whichever  it  may  prove 
to  be,  the  best  procedure  undoubtedly  is  to  make  a  vaccine 
from  the  organism  thus  isolated.      In  the  case  of  the 
Bacillus  septus  a  stock  vaccine  may,  however,  be  employed, 
in  case  of  objection  being  taken  to  the  expense,  inasmuch 
as  it  appears  to  be  a  morphological  entity.     This  perhaps 
holds,  but  to  a  less  degree,  in  the  case  of  the  Micrococcus 
catarrhalis  ;  but  so  great  are  the  variations  exhibited  by 
different  members  of  the  bacillus  of  Friedlander  group 
that  but   slight  success    may  be  anticipated   from   any 
vaccine  other  than  that  prepared  from  the  patient's  own 
organism,   unless    it    be   one    of    high  poly  valency.      If 
possible,  the  patient  should  remain  in  bed  for  at  least 
twenty-four  hours  subsequent  to  injection  ;    but  should 
this  not  be  possible,  then  as  soon  as  he  has  arrived  at  home 
for  the  evening  is  a  suitable  opportunity  for  injection. 


The  negative  phase  with  an  appropriate  dose  being  usually 
over  within  twelve  or  eighteen  hours,  risk  of  relapse  is 
only  slight  by  eight  or  nine  o'clock  the  next  morning. 
The  dose  I  usually  employ  is  150,000,000  or  200,000,000 
of  any  of  the  above  organisms. 

I  have  now  treated  a  considerable  number  of  cases  in 
this  way,  and  always  with  very  marked  success.     Some 
people  appear  to  be  immune  to  all   '  cold  '   organisms, 
others  are  especially  susceptible  to  one  of  the  group,  yet 
others  to  more  than  one.     Injection  during  the  subacute 
stage  of  an  attack  in  those  who  fall  under  the  second  of 
these  categories  has,  in  each  instance,  not  only  markedly 
cut  short  the  attack,  but  entirely  prevented  the  onset  of 
others,  even  for  a  period  of  over  a  year.     In  those  who 
are  susceptible  to  more  than  one  of  these  organisms  any 
given  attack  may  be  due  to  one  only  of  their  particular 
enemies  or  to  more  than  one.     Each  organism  produces 
its  own  type  of  cold,  and  from  the  unusual  features  pre- 
sented  mixed  infection   can  be   diagnosed   even   before 
smears   or   cultures   have   been  examined.     Should   one 
organism  only  be  found  in  the  particular  attack,  then  a 
vaccine  of  that  organism  alone  may  be  given,  or  to  it  may 
be  added  a  stock  vaccine  of  the  other  organism  to  which 
the  patient  is  also  susceptible.     In  this  way  the  attack 
may  be  shortened,  and  immunity  also  secured  against 
future  ones.      Should  mixed  infection  be  found  present, 
then,  of  course,  a  mixed  vaccine  should  be  administered. 
The  following  are  a  few  examples  of  cases  treated  ac- 
cording to  this  method. 

Case  1  had  for  years  been  very  susceptible  to  catarrhal 
attacks,  which  began  in  the  naso-pharynx,  producing  a 
distinctly  sore  throat.  A  train  journey,  even  for  a  few 
miles,  would  infallibly  induce  such  an  attack. 


iss  VACCIXE  THERAPY 

Advantage  was  taken  of  an  acute  attack  to  isolate  the 
Bacillus  septus,  which  had  been  diagnosed  beforehand  as 
the  causal  agent.  Upon  the  third  day  of  the  attack  an 
injection  of  250,000,000  organisms  was  given.  Two  days 
later  the  patient  was  well.  Soon  after  he  was  called  upon 
to  undertake  a  long  and  tedious  train  journey  in  the  depth 
of  winter.  For  the  first  time  for  years,  no  cold  resulted, 
and  during  the  subsequent  nine  months,  despite  frequent 
train  journeys,  he  remained  entirely  immune.  On  one  or 
two  occasions  an  impending  attack  was  felt,  but  imme- 
diately aborted. 

Case  2  had  at  least  half  a  dozen  acute  colds  every 
whiter,  always  of  the  same  type,  obviously  due  to  the 
Bacillus  septus.  At  the  beginning  of  last  winter  an  un- 
usually severe  but  typical  attack  came  on,  and  the  Bacillus 
septus  was  isolated.  Upon  the  second  day  of  the  attack 
his  index  was  0-94.  Upon  the  fifth  day  he  felt  very  bad 
indeed,  and  accordingly  275,000,000  organisms  were 
injected.  Improvement  began  within  twenty-four  hours, 
and  was  complete  within  forty-eight. 

3  days  after  injection  the  index  was  1*7 

13  ,,  „  „  „          1-1 

Although  the  index  would  thus  appear  to  have  returned 
to  normal  within  a  fortnight,  the  immunity  conferred 
lasted  throughout  the  whole  winter  despite  repeated 
exposure  to  contagion. 

Case  3  had  had  four  attacks  of  extreme  severity  within 
nine  months.  Upon  one  occasion  the  bacillus  of  Fried- 
lander  and  Bacillus  septus  were  both  isolated,  upon  the 
second  and  third  only  the  bacillus  of  Friedlander.  Hardly 
was  the  patient  convalescent  from  the  third  attack,  which 
was  one  of  the  most  severe  colds  I  have  ever  seen,  all  the 
accessory  sinuses  and  middle  ear  being  involved,  when 


THE  OPSONIC  TREATMENT  OF  CATARRH     189 

a  fourth  attack  came  on.  Upon  this  occasion  the  bacillus 
of  Friedlander  and  Micrococcus  catarrhalis  were  present  in 
about  equal  numbers.  The  prostration  of  the  patient  was 
so  extreme  that  I  decided  not  even  to  delay  while  a 
vaccine  was  prepared,  but  on  the  fourth  day  of  the  attack 
250,000,000  each  of  stock  vaccines  of  the  bacillus  of 
Friedlander  and  Micrococcus  catarrhalis  were  administered. 

For  forty-eight  hours  the  patient  was  very  bad,  but 
then  began  to  improve,  and  mended  rapidly.  Four  months 
later  she  informed  me  that  on  several  occasions  she  had 
felt  one  of  her  old  attacks  coming  on,  but  in  each  instance 
it  had  been  aborted  completely  within  two  or  three  hours. 

Case  4  had  been  a  martyr  to  repeated  attacks  of 
'  Friedlander  '  colds  for  years.  The  organism  was  isolated 
during  an  acute  attack  two  years  ago  and  two  injections 
given,  with  the  result  that  only  one  slight  attack  has 
occurred  in  all  the  subsequent  interval,  and  this  yielded 
to  a  single  injection. 

Numerous  other  cases  have  been  similarly  treated,  and 
all  have  the  same  tale  to  tell — subsequent  immunity 
from  attacks.  How  long  such  immunity  lasts  it  is  im- 
possible to  say,  but  it  is  hardly  advisable  to  allow  more 
than  three  months  to  pass  before  giving  a  fresh  injection. 
A  vaccine  once  made  will  keep  indefinitely,  so  that  this 
trouble  and  expense  need  only  once  be  incurred  in  the 
majority  of  cases. 

THE  OPSONIC  TREATMENT  OF  TEACHEAL  CATARRH. 

Tracheal  catarrh,  as  we  have  seen,  is  usually  initiated 
by  the  Micrococcus  catarrhalis  ;  unfortunately,  however, 
secondary  infection  by  other  organisms  often  adds  a 
complicating  factor.  The  treatment  is  rather  difficult  and 
results  not  very  encouraging  ;  the  best  that  can  be  hoped 


190  VACCINE  THERAPY 

for   is   diminished   secretion    and    comparative    freedom 
from  acute  attacks  of  tracheitis. 

Treatment  may  be  carried  out  either  by  means  of  a 
vaccine  prepared  only  from  the  Micrococcus  catarrhalis 
isolated  from  a  suitable  specimen  of  tracheal  mucus,  or  by 
a  combined  vaccine  of  the  various  organisms  present.  In 
the  former  case  injection  is  begun  with  150.000,000  to 
250,000.000  organisms,  and  is,  of  course,  controlled  by 
determinations  of  the  index  to  the  Micrococcus  catarrhalis. 
In  the  latter  case  a  minimal  dose  of  250,000,000  of  the 
mixed  organisms  is  used  at  first.  Inasmuch  as  the  esti- 
mation of  the  indices  to  the  various  organisms  would  be  far 
too  tedious,  that  to  one  alone  may  be  selected — best  to 
the  Micrococcus  catarrhalis.  A  tri-weekly  interval  between 
injections  will,  however,  prove  sufficiently  accurate.  By 
means  of  such  a  combined  vaccine  I  have  secured  a  certain 
measure  of  success  in  two  cases  of  chronic  tracheitis, 
diminishing  the  discharge,  and  preventing  the  occurrence 
of  any  acute  exacerbations.  In  a  third  case  cure  was  com- 
plete. That  extremely  troublesome  complaint  of  children 
whooping-cough  would  appear  to  offer  exceptional  oppor- 
tunities for  opsonic  treatment.  So  far  as  I  am  aware  no 
experiments  have,  however,  been  made  in  this  direction. 


THE  TREATMENT  OF  CHRONIC  NASAL  CATARRH. 

This,  as  has  been  mentioned,  is  apparently  always  due 
to  the  bacillus  of  Friedlander.  In  cases  where  the 
accessory  air  sinuses  are  not  involved,  complete  cure, 
both  of  the  chronic  attack  and  of  the  acute  exacerbations, 
is  to  be  expected  from  opsonic  treatment  and  daily  douch- 
ing with  weak  antiseptic  washes,  such  as  glycothymoline. 
By  these  means  I  have  completely  cured  cases  of  even 


THE  OPSONIC  TREATMENT  OF  CATARRH     191 

ten  years'  standing.  The  index  in  such  cases  is  usually 
above  normal  and  between  1'2  and  l-4.  A  dose  of 
250,000,000  of  the  patient's  own  organism  will  usually 
raise  this  to  2'5  or  over,  and  produce  marked  improve- 
ment within  a  week.  Two  or  three  such  injections  should 
prove  sufficient. 

When,  however,  extension  has  taken  place  to  the 
frontal,  ethmoidal,  or  antral  sinus,  the  case  is  very  much 
more  difficult.  In  two  such  cases  of  about  twenty  years' 
standing  I  have  sterilized  the  nose  by  adequately  raising 
the  index,  only,  however,  to  find  it  reinfected  in  a  month 
or  two  from  the  accessory  sinuses.  Could  free  drainage 
from  these  be  secured,  complete  cure  might  be  expected  ; 
as  it  is,  the  poor  blood-supply  and  lymph-flow  to  the 
parts  do  not  bring  sufficient  opsonin  to  insure  the  death 
of  the  infecting  organisms.  Perhaps  very  prolonged 
treatment  might  secure  this  much-desired  result.  One  very 
important  result  is,  however,  certainly  secured,  and  that 
is  the  prevention  of  acute  outbursts  of  the  nasal  catarrh. 

It  remains  to  mention  that  the  list  of  organisms  given 
above  as  being  capable  of  the  production  of  acute  nasal  and 
tracheal  catarrh  is  not  quite  complete.  It  comprises  all 
the  organisms  met  with  by  the  author  during  four  years 
extensive  experience  of  London  epidemics.  Benham l 
has  recorded  an  epidemic  occurring  in  Brighton,  which 
appeared  to  be  due  chiefly  to  the  Micrococcus  para- 
tetragenus,2  which  he  succeeded  in  isolating  from  a  number 
of  his  cases.  He  informs  me  that  the  symptoms  due  to 
this  organism  closely  resemble  those  I  have  described  as 
characteristic  of  the  Micrococcus  catarrhalis. 

1  Proc.  Brighton  and  Sussex  Med.-Chir.  Soc.,  1907-08,  p.  84. 

2  Besancon  and  De  Jong :  Bull.  Soc.  Med.  Hop.  de  Paris,  March  2 
and  16,  1905. 


CHAPTER  XII 

THE  COLON,  TYPHOID,  AND  DYSENTERY  GEOUPS 

THE  investigations  of  Gaertner,  Achard  and  Bensusan 
(1896),  Gwyn  (1898),  Schottmuller  (1900),  Kurth  (1901), 
Bryon  and  Kayser  (1902),  and  others  have  revealed  the 
existence  of  several  organisms  which  occupy  an  inter- 
mediate position  between  the  Bacillus  coli  communis  on  the 
one  hand  and  the  Bacillus  typhosus  on  the  other.  Some 
of  these  in  their  characteristics  more  nearly  resemble  the 
colon  bacillus,  and  are  therefore  known  as  paracolon  bacilli ; 
others  more  nearly  resemble  the  Bacillus  typhosus,  and 
are  known  as  paratyphoid  bacilli  (A  of  Bryon  and  Kayser, 
B  of  Schottmuller).  In  addition  to  these  are  the  various 
members  of  the  dysentery  group  (Shiga,  Flexner,  Hiss, 
Kruse). 

The  fact  that  these  intermediates  are  capable  of  causing 
lesions  in  the  human  subject,  as  yet  imperfectly  defined, 
causes  them  to  assume  an  added  importance.  The 
differentiation  of  the  various  members  of  this  group  the 
one  from  the  other,  is  by  no  means  easy,  and  hardly  comes 
within  the  scope  of  this  small  book.  For  convenience  the 
Colon,  Typhoid,  and  Dysentery  groups  will  be  described 
as  if  sharply  defined  from  each  other. 

I.  THE  BACILLUS  COLI  COMMUNIS  GROUP. 

The  Bacillus  coli  communis  and  its  near  allies  are 
especially  associated  with  disease  of  the  abdominal 

192 


THE  BACILLUS  COLI  COMMUNIS  193 

organs,  setting  up  such  conditions  as  peritonitis,  cystitis, 
urethritis,  endometritis,  abscesses  in  and  around  the 
kidneys,  enteritis,  perityphlitis,  and  inflammation  of 
the  gall-bladder  and  its  ducts.  It  also  occasionally  is 
the  cause  of  empyema,  puerperal  fever,  and  even  suppura- 
tive  periostitis. 

The  first  cases  of  the  successful  application  of  vaccine 
therapy  to  coli  infections  were  those  recorded  by  Wright1 
as  under  : 

1.  One  of  cholecystitis,  which  had  continued  for  sixteen 
years. 

2.  One  of  acute  coli  infection  of  the  biliary  passages, 
where,  after  removal  by  operation  of  an  impacted  calculus, 
the  fever  and  jaundice  continued,  and  the  bile  was  flowing 
away  through  the  external  wound,  probably  from  plugging 
of  the  bile-duct  by  inspissated  mucus. 

3.  One  which  had  been  operated  upon  two  months 
previously,   fourteen    stones    being    removed    from    the 
gall-bladder.     The  sinus  remained  open,  and  the  patient 
made  little  improvement.     An  injection  of  200,000,000 
organisms  was  given,  and  the  index  raised  to  1'8.   Closure 
of  the  sinus  was  followed  by  a  rise  of  temperature  and 
reopening   of   the    sinus.      A  second  injection  produced 
reclosure  of  the  sinus.    A  rigor  then  occurred,  and  the  sinus 
again  opened.     Owing  to  self -inoculation  the  index  rose 
to  4,  subsequently  falling  with  final  closure  of  the  sinus. 

Among  the  cases  subsequently  recorded  the  following 
may  be  mentioned  : 

Western  (loc.  cit.)  mentions  two  cases.  The  first  had 
had  cystitis  for  fifteen  months,  and  had  been  treated  with 
urinary  antiseptics  without  any  benefit.  Three  months' 
vaccine  treatment  caused  complete  disappearance  of  the 

1  Pathological  Society,  January  16,  1906. 

13 


194  VACCIXE  THERAPY 

Bacillus  coli  communis  from  the  urine,  and  there  has  been 
no  recurrence. 

The  second  had  had  cystitis  for  ten  months.  Vaccine 
treatment  was  incomplete,  but  had  produced  very  marked 
improvement. 

Turton  (loc.  cit.)  records  four  cases  : 

Xo.  1  had  been  operated  on  for  gall-stones,  but  the  pain, 
sickness,  and  rigors  persisted,  in  so  much  that  the  patient 
was  not  expected  to  live.  Three  injections  of  Bacillus 
coli  communis  vaccine  were  given.  After  the  first  the  rigors 
ceased,  and  in  four  weeks  the  patient  was  perfectly 
well. 

Xos.  2  and  3  were  cases  of  appendicular  abscess.  In 
one  the  condition  was  desperate,  but  both  did  well. 

No.  4  was  a  case  of  cystitis  of  six  months'  duration, 
which,  after  eight  injections,  cleared  up  completely". 

Butler  Harris1  draws  attention  to  the  interesting  fact 
that  in  many  cases  of  slight  endometritis  with  cervical 
catarrh  the  colon  bacillus  is  present,  and  fall  in  the  index 
to  this  organism  is  coincident  with  depression  of  the 
local  and  general  condition.  He  finds  that  5.000.000 
of  a  vaccine  given  a  week  after  the  period  and  repeated 
a  week  before  will  cure  the  local  infection  and  improve 
the  general  health.  The  treatment  has,  however,  to  be 
continued  for  a  considerable  time,  perhaps  six  months. 
He  also  states  that  in  mucous  colitis  good  results  have 
been  obtained. 

Bonney2  draws  attention  to  the  grave  import  of  the 
Bacillus  coli  communis,  complicating  a  primary  infection 
by  streptococci  or  pneumococci  hi  puerperal  fever.  The 
colon  bacillus  alone  may,  however,  be  responsible  for  this 
condition. 

1  Practitioner,  May,  1908,  p.  647. 
3  Clinical  Journal,  August  19,  1908. 


THE  BACILLUS  COLI  COMMUNIS  195 

The  scope  for  vaccine  therapy  in  this  severe  infection 
would  appear  to  be  great,  but  accurate  diagnosis  of  the 
infecting  organisms  in  a  prime  necessity. 

Wright  and  his  co-workers  have  recently  been  applying 
index  determinations  as  a  diagnostic  aid  in  cases  of 
supposed  appendicitis  and  appendicular  abscess. 

The  advisability  of  raising  the  opsonic  index  to  the 
colon  bacillus,  prior  to  abdominal  operations  in  cases 
where  contamination  of  the  wound  is  feared,  is  worthy 
of  earnest  consideration.  A  dose  of  50,000,000  to 
100,000,000  of  vaccine  three  to  seven  days  previously 
will  suffice. 

The  following  case  of  infection  by  the  Bacillus  coli 
communis  is  not  without  interest :  The  patient  was  sent 
to  me  by  Mr.  Wyndham  Powell,  suffering  from  subacute 
urethritis,  for  treatment  with  a  gonococcal  vaccine.  Four 
injections  were  given,  the  index  being  raised  from  0-37 
to  1'6.  The  urethral  condition  was  decidedly  improved, 
and  the  discharge  practically  ceased.  Considerable  dis- 
comfort, however,  was  felt  in  the  region  of  the  prostate, 
and  finally  culminated  in  an  attack  of  acute  prostatitis 
and  cystitis.  Nothing  definite  could  be  felt  per  rectum. 
The  colon  bacillus  was  isolated  from  the  urine,  and 
200,000,000  of  an  autogenous  vaccine  given.  A  rigor 
and  severe  general  disturbance  resulted.  This  would 
appear  to  be  especially  liable  to  happen  in  this  infection 
and  to  denote  closure  of  a  sinus  or  suppressed  discharge, 
and  re-examination  per  rectum  revealed  a  small  nodule 
in  the  prostate.  Upon  this  breaking  down  and  discharging, 
improvement  began,  and  two  injections,one  of  100,000,000, 
the  other,  fourteen  days  later,  of  150,000,000,  resulted 
in  cure. 

Cases  of  bacilluria  are  commonly  due  to  Bacillus  coli 

13—2 


196  VACCINE  THERAPY 

cowTOttws,especially  when  cystitis  complicates  tuberculosis 
of  the  bladder  or  kidney.  In  these  instances  little  progress 
is  often  made  under  tuberculin  treatment  alone.  Upon 
attention  being  simultaneously  directed  to  the  colon 
infection,  marked  improvement  soon  results. 

Owing  to  the  apparent  liability  to  rigors  and  great  con- 
stitutional disturbance  of  these  cases  when  an  injection 
results  in  suppressed  discharge,  an  initial  dose  of 
50,000.000  should  not  be  exceeded  ;  subsequently  larger 
doses  at  ten  days'  interval  are  to  be  recommended. 
The  best  results  will  only  be  obtained  by  the  use  of  an 
autogenous  vaccine. 

II.  INFECTIONS  BY  THE  TYPHOID  GROUP  OF  BACILLI. 

The  most  important  members  of  this  group  are  the 
Bacillus  typhosus  abdominalis  (Eberth),  the  Bacillus  para- 
typhosus  A  (Bryon  and  Kayser),  and  Paratyphosus  B 
(Schottmuller).  Other  slightly  variant  forms  have  also 
been  described.  The  practical  importance  of  the  dis- 
covery of  these  different  members  is  very  great,  and 
especially  with  regard  to  the  question  of  the  production  of 
anti-typhoid  immunity.  Epidemics  of  pseudo-typhoid 
fever  have  been  described  from  Germany.1  France,  and 
America,  and  isolated  cases  have  been  reported  in  Great 
Britain,  India,  etc.  The  paratyphoid  fevers  have  occurred 
in  series  of  true  enteric  fever,  in  house  epidemics,  and 
under  circumstances  which  point  to  the  disease  being 
sometimes  water-borne. 

The  clinical  features  have  been  very  variable,  but  three 
types  may  be  described  : 

Type  I.  closely  resembles  mild  typhoid  fever,  and  can 

1  Hunerman,  Zeitsclirift  f.  Hyg.  u.  Infect.  Krankli.,  1902,  Bd.  xl., 

l>  .V.^2 ;  and  Schottmuller. 


THE  TYPHOID  GROUP  197 

only  be  distinguished  by  failure  of  the  blood-serum  to 
agglutinate  the  Bacillus  typhosus,  and  its  power  to 
agglutinate  one  of  the  other  organisms  of  the  group.  As 
these  cases  all  recover,  the  anatomical  lesions  are  un- 
known. Haemorrhage,  phlebitis,  and  relapse  have  been 
described  as  complications. 

Type  II.  presents  the  clinical  features  of  septic  infection, 
and  resembles  the  so-called  typhoid  septicaemia,  or 
enteric  fever  with  intercurrent  or  terminal  sepsis.  These 
sometimes  end  fatally.  Enlargement  of  the  spleen  is  a 
constant  feature ;  sometimes  the  intestines  are  normal, 
at  other  times  ulcerated,  but  the  ulcers  are  like  those 
due  to  dysentery  rather  than  to  typhoid,  the  solitary 
follicles,  Peyer's  patches,  and  mesenteric  glands  being  as  a 
rule  unaffected. 

In  both  Types  I.  and  II.  rose  spots  and  sore  throat  are 
very  prominent  features. 

Type  III. — In  these  cases  the  organisms  have  been 
found  in  abscesses  in  patients  in  whom  no  history  of 
enteric  fever  was  obtainable. 

Both  in  true  enteric  and  in  the  fevers  of  Types  I.  and  II. 
the  organisms  can  be  almost  invariably  isolated  from  the 
blood  according  to  the  following  method  :  The  medium 
employed  is  ox  bile,  90  c.c.  ;  glycerine,  10  c.c.  ;  peptone, 
2  c.c.  Twenty  c.c.  of  this  are  put  into  small  flasks  and 
sterilized.  About  9  c.c.  of  blood  is  then  withdrawn  from 
a  vein  in  the  antecubital  fossa,  with  aseptic  precautions, 
and  3  c.c.  run  into  each  of  three  flasks,  which  are  then 
incubated  for  twelve  to  twenty-four  hours.  Stroke  cul- 
tures are  then  made  on  a  litmus  lactose  agar  plate,  upon 
which  growth  may  often  be  seen  in  six  hours. 

Coleman  and  Buxton1  employed  this  method  in  a  large 

1  American  Journal  of  Medical  Science,  June,  1907. 


198  VACCINE  THERAPY 

series  of  cases,  and  isolated  the  organism  in  every  instance 
before  the  second  week  of  illness,  and  often  before  the 
serum  reaction  developed.  After  the  second  week  there 
are  much  fever  organisms  in  the  blood.  Ninety  per  cent, 
of  thirty- three  relapses  also  gave  a  positive  result. 

Failing  to  isolate  the  organisms  by  blood-culture,  it 
remains  to  attempt  their  isolation  from  the  urine  and 
faeces  according  to  the  approved  methods. 

Having  obtained  a  culture,  test  is  then  made  for  the 
Widal  reaction,  both  with  the  organism  and  with  a 
standard  strain  of  the  Bacillus  typhosus.  For  it  must  not 
be  forgotten  that  the  patient  may  be  infected  with  both 
the  Bacillus  typhosus  and  Paratyphosus.1 

In  Europe  the  Paratyphosus  B  appears  to  be  the 
commoner.  In  India,  Semple2  found  the  Paratyphosus  A 
in  four  cases,  the  Paratyphosus  B  in  two  cases. 

Antityphoid  Immunization. 

Of  the  bearing  of  these  results  upon  the  statistical  side 
of  therapeutical  immunization  against  enteric  fever  sight 
must  not  be  lost.  As  to  the  merits  or  demerits  of  the 
procedure,  considerable  diversity  of  opinion  has  existed. 
The  latest  statistics,  and  especially  those  recorded  by 
Luxmore  3  in  the  case  of  the  17th  Lancers,  are  much  more 
favourable  ;  but  before  any  definite  conclusions  can  be 
formed  it  is  obviously  necessary  to  take  into  account  the 
possibility  of  a  given  epidemic,  or  of  a  certain  number  of 
cases  in  such  an  epidemic  being  really  due  to  one  or  other  of 

1  For  such  a  case  see  Scientific  Memoirs  of  the  Medical  Depart- 
ment of  Government  of  India,  No.  32,  1908,  p.  81. 

a  Ibid. 

'  Journal  of  Royal  Army  Medical  Corps,  January  to  June,  1907, 
p.  492. 


THE  TYPHOID  GROUP  199 

the  paratyphoid  bacilli,  and  to  this  hitherto  no  attention 
has  been  paid.  The  advisability  of  employing  a  vaccine 
containing  not  only  the  Bacillus  typhosus,  but  also  the 
-several  paratyphoid  bacteria,  is  worthy  of  consideration.1 

Preparation  of  Antityphoid  Vaccine  :  its  Effects  and 
Method  of  Use. 

The  mode  of  preparation  approved  by  the  Army 
Council  is  as  follows  :  A  non-virulent  strain  is  grown  on 
broth  of  a  definite  reaction,  and  incubated  at  37°  C.  for 
twenty-four  to  forty-eight  hours.  In  order  to  encourage 
free  growth  special  flasks  are  used,  giving  a  shallow  layer 
of  about  1  inch  of  medium,  so  as  to  permit  of  good  aeration, 
this  being  essential  to  obtain  maximum  development. 
The  contents  of  the  flask  are  then  standardized  in  the 
usual  way,  and  sterilized  by  heating  on  a  water-bath  for 
one  hour  at  53°  C.  Sterility  is  proved  by  aerobic  and 
anaerobic  cultures,  and  0-25  per  cent,  lysol  added.  The 
vaccine  is  diluted  if  necessary  so  as  to  contain 
1,000,000,000  bacteria  per  c.c.,  and  put  up  in  glass  bulbs 
containing  1  c.c.  and  \  c.c.  respectively. 

To  insure  antityphoid  immunity  the  smaller  dose  is 
injected  into  the  flank  or  side  of  the  arm,  and  the  patient 
put  to  bed  for  twenty-four  hours,  as  sometimes  consider- 
able constitutional  disturbance  results.  Ten  days  later 
the  larger  dose  is  given,  and  should  produce  no  ill  effects. 

The  effects  of  such  inoculation  have  now  been  fully 
studied.  The  method  of  estimating  the  typho-opsonic 
index  is  a  special  one,  and  will  be  found  in  the  Appendix. 
The  phagocytic  index2  appears  to  be  depressed  for 

1  A  vaccine  of  this  composition  can  now  be  obtained  from  W.  H. 
Martindale,  10,  New  Cavendish  Street. 

2  Harrison,  Journal  ofBoyal  Army  Medical  Corps,  May,  1907,  p.  472. 


200  VACCINE  THERAPY 

three  to[six  weeks  after  commencing  treatment,  and  then 
rises  above  normal.  There  is  also  a  marked  rise  of  four 
to  six  times  in  the  bactericidal  power. 

The  duration  of  the  immunity  thus  conferred  has  been 
studied  by  Harrison.1  He  found  that  evidence  of  a 
bactericidal  activity  higher  than  normal  and  of  agglu- 
tinins  could  be  obtained  from  the  serum  of  men  who  had 
been  inoculated  as  long  as  six  years  previously  ;  but 
whether  the  protection  that  so  remains  will  still  suffice  to 
ward  off  an  attack  of  enteric  fever  is  not  yet  known. 

The  role  of  agglutinins  and  bactericidal  substances  in 
the  production  of  typhoid  immunity  is  still  unsettled. 
Fhus,  Jorgensen2  found  that  the  agglutinating  power 
usually  declines  after  the  third  week,  and  that  a  high 
agglutinative  power  does  not  appear  to  protect  against 
relapse  or  recurrence,  and  the  same  is  possibly  true  of  the 
bactericidal  substances  ;  while  Stern  and  Korte3  found 
in  a  patient,  whose  serum  revealed  the  highest  bactericidal 
power  ever  observed  by  them,  that  a  relapse  developed 
eight  days  later.  A  possible  fallacy  in  these  observations 
lies  in  the  fact  that  they  were  conducted  '  in  vitro.''  Topfer 
and  Jaffe4  found  with  the  Pfeiffer  method  '  in  vivo '  that 
the  serum  of  convalescents  was  more  effective  bacteri- 
cidally  than  that  of  acutely  ill  typhoid  patients  ;  while 
Klein,5  and  Neufeld  and  Kuhne,6  have  found  increase  of 
opsonin,  and  especially  of  specific  opsonin,  in  the 
'  immune  '  sera  of  convalescent  cases. 

1  Journal  of  Royal  Army  Medical  Corps,  May,  1907,  p.  472. 

2  Centralb.  f.  Bakt.  u.  ParasiL,  Jena,  1908,  Bd.  xxxviii.,  p.  475. 
»  Berlin.  Klin.  WocJi.,  1904,  Bd.  xli. 

4  Zeitschrift  f.  Hyg.  u.  Infect.,  Leipzig,  1906,  Bd.  lii.,  p.  393. 
6  Johns  Hopkins  Hospital  Bulletin,  June  and  July,  1907,  p.  245. 
6  Arb.  a.  d.  k.  Gesundheitsamte,  Berlin,  Bd.  xxv.,  p.  164. 


THE  TYPHOID  GROUP  201 

Typhoid  Carriers. 

A  careful  study  of  recent  epidemics  has  revealed  the 
fact  that  in  many  cases  these  have  been  initiated  by  the 
contamination  of  food  or  water  supplies  from  the  urine  or 
faeces  of  old  enteric  patients,  who  in  some  instances  have 
exhibited  no  symptoms  for  many  years.  Semple  has 
carefully  investigated  several  of  these  cases,  and  finds  that 
this  discharge  of  bacteria  may  be  very  markedly  inter- 
mittent, occurring  at  intervals  perhaps  of  a  month  apart. 
He  explains  this  as  follows  :  The  typhoid  bacilli  during 
an  attack  are  deposited  in  the  liver  or  kidney  ;  in  the 
former  case  they  may  infect  the  bile,  a  most  favourable 
medium  for  their  growth,  and  are  poured  into  the  intestine 
and  excreted  in  the  faeces.  In  the  latter  case  an  infected 
focus  breaks  down  at  intervals  and  infects  the  urine.  In 
confirmation  of  this  view  is  the  fact  that  he  examined  the 
bile  in  seventeen  fatal  cases  of  enteric,  and  found  it  infected 
in  ten  of  these. 

As  a  result  of  these  investigations,  the  question  of  careful 
systematic  testing  of  the  urine  and  faeces  of  convalescent 
typhoid  cases,  and  of  the  therapeutic  inoculation  of  all 
such  as  are  found  to  continue  to  be  infected,  becomes  a 
very  important  one. 

The  treatment  of  enteric  fever  with  specific  sera,  filtrates, 
and  residues  has  been  studied  in  a  series  of  204  patients  by 
Richardson.1 

Of  these  204  cases,  74  underwent  ordinary  routine 
treatment  ;  35  routine  treatment,  together  with  the  sera 
of  immunized  horses  given  in  various  ways  ;  74  routine 
treatment,  combined  with  subcutaneous  injections  of 
about  3  c.c.  daily  of  a  sterile  filtrate  of  bouillon  cultures  ; 
1  Boston  Medical  and  Surgical  Journal,  vol.  cvii.,  No.  14,  p.  449. 


202  VACCINE  THERAPY 

21  routine  treatment,  combined  with  daily  subcutaneous 
doses  of  2  to  10  c.c.  of  typhoid  vaccine. 

The  administration  of  these  immunizing  agents  was 
uncontrolled  by  index  determinations. 

His  conclusions  are  most  guarded,  but  are  as  follows  : 
That,  despite  the  handicap  to  specific  therapy  in  the 
difficulty  of  early  diagnosis— 

1.  Specific  therapy,  confined  to  the  original    disease, 
increases,  apparently,  the  tendency  to  relapse. 

2.  Inoculation  with    typhoid  vaccine  continued  into 
convalescence  largely  eliminates  the  risk  of  relapse. 

3.  Antityphoid    serum    is    no    more    effective    than 
filtrates  or  vaccine,  and  is  much  more  expensive. 

4.  Typhoid  filtrates  may  exert  a  powerful  effect  upon 
the  clinical  course,   their  use  being  followed  in  many 
instances  by  chills  or  rise  in  pulse  and  temperature,  these 
being  often  followed  in  their  turn  by  marked  fall  in 
pulse-rate  and  temperature,  and  a  general  improvement 
in  the  clinical  picture. 

5.  That  a  vaccine  seems  to  make  the  typhoid  process 
longer,  but  milder,  and  is  apparently  very  effective  in  the 
prevention  of  relapses. 

Vaccine  therapy  also  finds  a  place  hi  the  treatment  of 
cholecystitis,  which  is  much  more  frequently  due  to  the 
Bacillus  typhosus  than  is  commonly  supposed. 

In  localized  infections  the  same  dosage  as  for  Bacillus 
coli  communis  may  be  employed. 


III.  THE  DYSENTERY  GROUP. 

Of  the  various  forms  of  dysentery,  the  only  one  with 
which  vaccine  therapy  is  concerned  is  the  bacillary. 
Several  closely-allied  bacteria,  differing  mainly  in  their 


THE  DYSENTERY  GROUP  203 

sugar  and  agglutinative  reactions,  have  been  described  in 
different  epidemics  by  Shiga,  Kruse,  Flexner,  Hiss,  and 
Strong,  and  bear  their  respective  names. 

The  chief  work  from  the  point  of  view  of  immunization 
by  means  of  vaccines  has  been  done  by  Captain 
W.  H.  C.  Forster,  of  the  Indian  Medical  Service.  During 
the  past  two  years  he  has  been  actively  engaged  upon 
the  subject,  and  to  his  publications  and  letters  I  am 
indebted  for  the  following  account  : 

Clinically,  bacillary  dysentery  may  be  divided  as 
follows  : 

CLASS.  I.  Acute  dysentery — 

1.  Gangrenous. 

2.  Non-gangrenous. 

CLASS.  II.  Chronic   dysentery,   which  may  be  sub- 
divided into — 

1.  Cases  of  weeks'  or  months'  duration,  in  which 

the  patient  is  still  passing  dysenteric  stools, 
either  continuously  or  intermittently. 

2.  Cases  of  years'  duration,  in  which  the  patient 

has  ceased  to  pass  dysenteric  motions,  and 
in  whom  the  symptoms  consist  of  flatulent 
diarrhoaa,  accompanied  by  abdominal  pain 
of  a  peculiar  type. 

Of  these,  the  following  are  suitable  for  vaccine  therapy  : 

The  non-gangrenous  cases  of  Class  I.  which  have 
resisted  treatment  for  seven  days,  and  in  which  the 
patient  is  not  obviously  moribund. 

Of  Class  II.  all  cases  are  suitable  except  those  in 
whom  the  bowel  is  so  extensively  damaged  by  chronic 
ulceration  as  to  render  hopeless  treatment  of  any  sort. 

Although  the  cases  treated  have  been  variously  in- 


204  VACCINE  THERAPY 

fected  by  the  following  different  strains — Kruse-Shiga, 
Flexner,  and  Y.  of  Hiss — the  vaccine  employed  has 
been  prepared  only  from  the  Kruse-Shiga  type  ;  so  that 
the  results  achieved  are  the  more  striking.  Uniformly 
satisfactory  results  have  been  obtained  and  recorded  by 
Forster,1  Gillitt,2  Stephen,3  Newman,4  Castellani,5  many 
of  the  cases  being  very  striking,  especially  in  the  chronic 
relapsing  ones,  in  which  all  medical  treatment  had  been 
unavailing.  Thus,  of  ten  such  chronic  cases  Forster 
completely  cured  seven,  these  remaining  perfectly  well 
for  twelve  months  after  treatment. 

In  the  Midnapore  Gaol  the  case  mortality  over  six 
years  averaged  6-3  per  cent.  ;  after  the  adoption  of 
Forster's  vaccine  it  fell  to  0-9  per  cent. 

The  scheme  of  treatment  laid  down  by  Forster  is  as 
follows  :  The  immediate  injection  of  acute  as  well  as  of 
chronic  cases  by  means  of  a  stock  vaccine,  given  in  small 
doses  at  fixed  intervals,  without  the  control  of  the  opsonic 
index.  Of  course  common  sense  must  be  applied  if 
clinical  symptoms  contra-indicate  the  repetition  of  a  dose 
at  a  given  time.  In  acute  cases  the  commencement  of 
vaccine  therapy  is  contra-indicated  from  the  fourth  to  the 
twenty-first  day. 

As  different  strains  of  the  organisms  vary  greatly  in 
their  toxicity,  and  as  toxic  strains  are  liable  to  produce 
very  violent  local  and  general  reaction,  even  in  small 
doses,  counting  methods  of  standardization  are  not  em- 
ployed, but  the  strength  of  the  vaccine  is  so  regulated  that 
the  minimum  lethal  dose  for  a  rabbit  of  1,200  to  1,400 

1  Indian  Medical  Gazette,  June,  1907,  p.  201. 

3  Ibid.,  January,  1908,  p.  12.  3  ibid.,  October,  1907,  p.  375. 

*  Lancet,  May  16,  1908,  p.  1410. 

5  Archivf.  Schiff  u.  Trop.  Hi/g.t  Bd.  xi,  Heft  3. 


THE  DYSENTERY  GROUP  205 

grammes  in  weight  is  not  less  than  0-4  c.c.  Of  such  a 
vaccine  his  dosages  are,  for  an  adult,  in  both  the  acute 
and  chronic  forms — 

First  dose  . .          . .          . .  O'l  c.c. 

Second  dose  . .          . .          . .          . .  0'2  c.c. 

Third  dose  0*3  c.c. 

Fourth  dose  . .          . .          . .          . .  0'4  c.c. 

For  females  a  slight  reduction  is  necessary. 

In  the  case  of  a  child  of  nine,  a  first  dose  of  0-05  c.c. 
was  given,  and  a  second  of  0-1  c.c.,  without  ill  effects  and 
with  a  good  result. 

The  doses  indicated  above  produce  practically  no 
negative  phase,  and  in  fourteen  days  the  immunity  is 
more  than  a  hundred  times  what  it  was  before  the  dose. 

Forster  employs  intervals  of  ten  days  between  the 
doses,  and  usually  proceeds  to  the  fourth  dose,  to  make 
sure  that  the  patient  has  got  rid  of  all  bacilli  and  is 
not  likely  to  become  a  chronic  '  carrier.'  If  it  be  neces- 
sary to  go  beyond  the  fourth  dose  with  increased  quan- 
tities, the  bowel  symptoms  must  be  carefully  watched, 
as  large  doses  are  very  toxic,  and  in  animals,  at  all  events, 
badly  tolerated.  In  man,  the  symptoms  of  over-dosage 
take  the  form  of  dysenteric  pains  in  the  bowel,  with 
diarrhoea  and  even  blood  and  mucus.  Most  doses  are 
followed  by  some  slight  symptoms  of  the  sort,  but  if  these 
are  severe  in  any  given  case,  a  reduced  dosage  must  be 
employed. 


CHAPTER  XIII 

INFECTIONS  DUE  TO   THE  MICEOCOCCUS  MELITENSIS, 

BACILLUS  PARALYTICANS,  MICROCOCCUS  NEOFOR- 

MANS,  MENINGOCOCCUS,  AND  ACTINOMYCOSIS 

THE  MICROCOCCUS  MELITENSIS. 

THE  fact  that  Malta  fever  is  a  systemic  infection  would 
seem  to  render  vaccine  therapy  inadvisable.  Wright, 
however,  advocates  its  use  in  comparatively  light 
attacks,  when  the  fever  is  likely  to  run  on  for  months 
without  any  severe  intoxication  of  the  system,  and  where 
the  imperfect  development  of  the  agglutination  reaction 
seems  to  indicate  that  the  immunizing  impulses  are  in 
default. 

He  has  successfully  treated  a  case  of  localized  infection 
supervening  upon  an  attack  of  Malta  fever. 

Bassett  Smith,1  following  up  the  apparently  successful 
treatment  by  Reid  of  nine  cases  of  Malta  fever  by  means 
of  a  vaccine,  observed  the  results  of  such  treatment  in 
sixty-one  cases,  to  which  224  injections  were  given. 
These  cases  comprised  all  grades  in  the  disease,  from  the 
severe  undulant  type  to  the  intermittent.  The  initial 
dose  employed  was  usually  about  50,000,000  organisms, 
and  this  was  but  rarely  exceeded,  the  interval  between  the 
injections  being  ten  days.  The  negative  phase  was 

1  Journal  of  Hygiene,  January,  1907,  p.  115. 
206 


THE  BACILLUS  PARALYTICANS  207 

frequently  very  short  or  altogether  absent,  a  steady  rise 
being  commonly  observed. 

No  relationship  was  found  to  exist  between  the  curves 
of  the  opsonic  indices  and  the  agglutination  reactions  of 
the  patient's  sera.  Bassett  Smith  concluded  that  the 
vaccine  treatment  of  Malta  fever  appears  in  a  certain 
number  of  cases  to  produce  a  beneficial  result,  the 
severity  of  the  symptoms  being  diminished,  the  general 
condition  improved,  and  the  duration  of  the  disease  cur- 
tailed ;  but  that  in  the  more  severe  type  of  case,  with 
high  fever  and  evidence  of  severe  intoxication,  the 
method  appears  to  have  a  deleterious  instead  of  a  favour- 
able action. 

I  would  suggest  that  the  more  frequent  administration 
of  much  smaller  doses,  as  in  streptoccocal  and  gonococcal 
septicaemias,  might  possibly  secure  more  favourable 
results. 

THE  BACILLUS  PARALYTICANS. 

Numerous  attempts  have  been  made  to  isolate  from 
the  blood  and  cerebro-spinal  fluid  of  cases  of  general 
paralysis  of  the  insane  and  of  tabes  dorsalis  an  organism 
or  organisms  which  might  prove  to  stand  in  a  causal 
relationship  to  this  disease  or  to  the  congestive  seizures. 

Ford  Robertson  and  McRae  claimed  to  have  demon- 
strated the  constant  presence  of  an  organism  of  the 
diphtheroid  group,  to  which  they  gave  the  name  Bacillus 
paralyticans,  in  the  blood,  cerebro-spinal  fluid,  and  brain 
tissues.  Other  observers,  among  whom  may  be  men- 
tioned Eyre  and  Flashman,  have,  however,  shown  that 
there  is  hardly  any  part  of  the  body  where  diphtheroid 
organisms  had  been  obtained  by  Robertson  in  cases  of 
general  paralysis  from  which  similar  organisms  could  not 


208  VACCINE  THERAPY 

be  obtained  in  cases  free  from  any  semblance  of  insanity. 
The  difficulties  in  technique  are  so  great,  and  the  risks  of 
contamination  in  taking  cultivations  so  considerable, 
that  variable  results  are  almost  inevitable  in  the  hands 
of  different  observers.  It  may  be  mentioned  that  the 
psychological  moment  for  taking  cultures  is  as  soon  as 
possible  after  a  congestive  attack,  for  leucocytosis  is 
rapidly  developed,  and  in  an  hour  or  two  the  phagocytic 
action  of  the  leucocytes  may  destroy  all  the  organisms  in 
the  blood-stream.  Sufficient  attention  to  this  point  does 
not  appear  to  have  been  paid  by  all  observers.  Ford 
Robertson  now  considers  that  a  second  organism,  to  which 
he  has  given  the  name  Bacillus  paralyticans  brews,  is  also 
concerned  in  the  production  of  a  certain  proportion  of 
cases  of  general  paralysis.  Candler1  altogether  failed  on 
forty-one  occasions  in  twenty-four  cases  to  find  either  of 
these  organisms,  while  G.  M.  Robertson2  upon  fifteen 
occasions  in  seven  cases  of  undoubted  general  paralysis 
recovered  a  diphtheroid  organism  from  the  blood  or 
cerebro-spinal  fluid,  which,  however,  appeared  to  differ 
from  either  of  Ford  Robertson's  forms.  Sufficient 
evidence  has  not  yet  been  accumulated  to  warrant  the 
view  that  any  definite  member  of  the  diphtheroid  group 
is  responsible  for  the  production  of  general  paralysis, 
although  it  seems  likely  that  the  presence  of  these  organ- 
isms is  more  than  a  coincidence,  and  important  discoveries 
may  soon  be  anticipated. 

O'Brien3  details  the  result  of  opsonic  determinations 
with  Ford  Robertson's  original  Bacillus  paralyticans  upon 
seven  cases  of  this  disease.  The  indices  showed  great 
fluctuations,  leading  him  to  the  conclusion  that  the  infec- 

1  Lancet,  August  17,  1907,  p.  450.  2  Ibid.,  p.  449. 

3  Journal  of  tlie  American  Medical  Association,  1906,  p.  2180. 


THE  MICROCOCCUS  NEOFORMANS         209 

tion  is  a  systematic  one.  Injections  of  a  vaccine  were 
given  about  every  fourteen  days,  and  marked  improve- 
ment in  the  symptoms  claimed  to  be  noticed. 

These  results  must  be  received  with  great  caution,  in 
view  of  Ford  Robertson's  modified  opinion  of  the  causal 
relationship  of  this  organism  to  the  disease,  and  in  con- 
sideration of  the  fact  that  remissions  in  the  course  of 
general  paralysis  are  very  common.  In  so  dread  a  disease 
no  chance  of  doing  good  should,  however,  be  neglected, 
and  in  the  event  of  the  isolation  of  a  diphtheroid  organism 
from  cultures  of  the  cerebro-spinal  fluid  taken  during  or 
immediately  after  a  congestive  attack,  the  administration 
of  a  vaccine  prepared  from  this  organism  would  appear 
to  be  a  justifiable — nay,  advisable — proceeding. 

THE  MICROCOCCUS  NEOFORMANS. 

The  contention  of  Doyen  that  this  organism  is  the  true 
cause  of  carcinomatous  tumours  has  not  been  accepted 
by  pathologists  in  this  country ;  for  not  only  is  it  found 
in  the  vicinity  of  carcinomata,  but  also  in  that  of  sarco- 
mata and  such  benign  growths  as  adenomata.  Inocula- 
tion experiments  upon  rats  and  mice  have  also  completely 
failed  to  produce  a  malignant  tumour. 

Successful  treatment  by  means  of  a  vaccine  was 
recorded  by  Wright  in  a  case  of  cancer  of  the  larynx. 
Death,  however,  ensued  in  about  six  months,  and  was 
found  post-mortem  to  be  due  to  cancer. 

Jacobs  and  Geets  1  recorded  the  results  of  treatment  in 
thirty-seven  cases  of  mammary  carcinoma.  They  regard 
the  Micrococcus  neoformans  as  the  cause  of  the  cancerous 
cachexia.  The  index  in  these  cases  was  found  usually 

1  Lancet,  April  7,  1906,  p.  964. 

14 


210  VACCINE  THERAPY 

to  be  below  0-8.  Cases  in  which  the  index  failed  to  rise 
after  two  injections  they  considered  hopeless  from  ex- 
haustion of  the  defensive  powers. 

The  results  of  treatment  seem  to  be  decrease  of  sur- 
rounding infiltration,  reduction  in  the  size  of  the  nodules, 
which  usually  become  freely  movable,  great  improvement 
in  the  patient's  appearance  and  general  condition,  and 
diminution  of  pain.  This  they  hold  to  be  the  time  for 
operation.  They  tabulate  then-  results  as  follows  : 

'  Cure  '  maintained  after  several  months  in       7  cases. 

Lasting  improvement  in      . .          . .  12      ,, 

Transient  result  in    . .          . .          . .          . .  7     „ 

No  result  in    ..          ..         ..          ..  11      ,, 

Total     ..          . .     37      „ 

The  opinion  at  the  London  Cancer  Hospital  is  that  as  a 
curative  agent  a  vaccine  of  the  Micrococcus  neoformans  is 
valueless,  and  its  employment  has  therefore  been  entirely 
abandoned  at  that  institution.  It  may,  however,  well 
be  left  to  any  inoperable  case  of  cancer  to  decide  whether 
employment  of  this  harmless  agent  shall  be  made,  in  the 
remote  hope  of  the  case  being  brought  within  the  zone  of 
operability.  Admitting  that  the  Micrococcus  neoformans 
is  not  the  cause  of  cancer,  it  cannot,  however,  be  denied 
that  it  is  almost  always  associated  with  the  cancerous 
tumour. 

THE  MENINGOCOCCUS. 

The  complete  failure  of  various  varieties  of  anti- 
meningococcic  sera  to  influence  favourably  the  course 
of  the  disease  during  the  recent  epidemics  at  Belfast  and 
Glasgow,  and  the  occasional  success  of  a  streptococcal 
vaccine  in  cases  of  streptococcal  septicaemia,  have  en- 
couraged efforts  in  a  similar  direction  hi  cases  of  cerebro- 


THE  MENINGOCOCCUS  211 

spinal  meningitis.  Bundle  and  Mottram l  have  recorded 
a  successful  result  in  a  case  in  which  the  prognosis  was 
distinctly  bad.  The  index  was  0*7  when  an  injection  of 
200,000  organisms  was  given  ;  next  day  it  had  risen  to 
1-5.  In  the  subsequent  twenty  days  four  doses  of 
500,000  organisms  were  given,  each  followed  by  negative 
and  positive  phases.  Recorded  cases  of  successful  treat- 
ment are  so  far  very  few,  but  I  have  heard  privately  of 
two  other  such  instances. 

Houston  and  Rankin,2  Fordyce,3  and  others  have 
studied  the  opsonic  and  agglutinative  power  of  the  blood- 
serum  and  cerebro-spinal  fluid  in  cases  from  various 
epidemics.  With  normal  serum  phagocytosis  is  ex- 
tremely slight,  and  does  not  occur  until  degeneration  of 
the  coccus  has  commenced.  This  is  true,  irrespective  of 
whether  the  organism  has  been  freshly  isolated  or  re- 
peatedly subcultured.  With  '  immune  '  sera  the  degree 
of  phagocytosis  very  rapidly  increases  with  the  extent 
to  which  the  organism  has  been  subcultured.  The  diffi- 
culty of  some  observers  with  clumping  of  the  emulsion 
is  very  greatly  obviated  by  employing  a  growth  six  to 
ten  hours  old  and  incubating  the  opsonic  mixture  for 
only  ten  minutes.  Employing  this  technique,  the  author 
has  not  experienced  the  slightest  trouble,  even  with  the 
most  freshly-isolated  organisms. 

At  the  very  onset  the  index  is  probably  low.  Thus, 
in  one  instance  Fordyce  found  an  index  of  only  0-4 
within  twenty-four  hours  of  onset.  Later  the  index  of 
the  blood-serum  rises  very  rapidly  and  within  five  or 
six  days  may  be  between  5  and  10.  Later  it  may  be  as 

1  Lancet,  July  27,  1907,  p.  220. 

2  British  Medical  Journal,  November  16,  1907. 

3  '  International  Clinics  '  (eighteenth  series),  vol.  i.,  p.  40. 

14—2 


L>12  VACCINE  THERAPY 

high  as  30  or  40.  The  agglutinative  power  of  the  serum 
is  also  very  marked.  In  convalescent  cases  these  typical 
reactions  disappear  rapidly.  The  cerebro-spinal  fluid 
has  very  much  lower  opsonic  and  agglutinative  power 
than  the  blood-serum,  and  may  even  have  none  at  all ; 
Houston  and  Rankin  conclude  that  these  reactions  are 
of  very  great  value  in  the  diagnosis  of  early  cases  of  true 
epidemic  cerebro-spinal  meningitis,  and  in  differentiating 
them  from  those  of  posterior  basic  meningitis,  which  are 
due  to  a  Gram-negative  coccus  very  closely  resembling 
the  true  meningococcus,  both  morphologically  and 
culturally. 

Owing  to  the  rapid  loss  of  virulence  on  the  part  of 
this  organism,  the  vaccine  should  be  prepared  from  a  first 
subculture,  if  possible,  and  preferably  from  the  patient's 
own  organism. 

The  appropriate  dosage  is  as  yet  uncertain.  It  is 
perhaps  advisable  to  begin  with  500,000  to  1,000,000,  and 
repeat  and  increase  as  the  index  or  clinical  symptoms 
indicate. 

The  benefit  observed  in  certain  instances  from  lumbar 
puncture  may  perhaps  be  due  to  replacement  of  cerebro- 
spinal  fluid  of  low  opsonic  power  by  fresh  fluid  with  more 
active  bactericidal  properties. 

ACTINOMYCOSIS. 

The  first  case  of  actinomycotic,  or  rather  strepto- 
trichotic,  disease  treated  by  means  of  a  vaccine  has  been 
that  of  the  lung,  and  probably  of  the  liver,  described 
by  Wynn.1  The  infection  probably  dated  back  at  least 
twelve  months,  and  six  months  prior  to  admission  to  hos- 
1  British  Medical  Journal,  March  7,  1908. 


ACTINOMYCOSIS  213 

pital  extension  seems  to  have  occurred  from  the  bronchi 
to  the  lung  tissue,  and  much  sputum  with  a  feculent  odour 
was  expectorated.  Subsequent  formation  of  an  empyema 
required  operation,  and  from  the  pus  a  pure  culture  of 
streptothrix  was  isolated,  and  a  vaccine  prepared  from  a 
forty-eight  hours'  old  agar  culture.  The  dose  employed 
for  each  inoculation  represented  O'OOl  milligramme  of 
bacterial  substance.  Attempts  were  made  to  estimate  the 
index,  which  was  approximately  0'3  on  January  3  and 
0'5  on  January  7  ;  on  January  8  the  first  inoculation  of 
OOOl  milligramme  was  given.  Twenty-four  hours  later 
the  negative  phase  was  apparently  over,  as  the  index  had 
risen  to  0'7,  and  by  January  16  was  1-2.  In  a  few  days 
the  cough  became  less  troublesome,  and  the  sputum  and 
discharge  of  pus  diminished  in  a  remarkable  way.  The 
temperature  dropped  from  over  100°  F.  to  normal,  and 
remained  normal  for  three  days.  Four  days  after  in- 
jection the  discharge  had  so  diminished  that  the  drainage- 
tube  was  removed.  A  slight  rise  of  temperature  resulted, 
and  on  the  18th  instant  a  second  inoculation  of  0-001 
milligramme  was  given.  Three  days  later  temperature 
was  again  normal,  and  remained  so.  Subsequent  injections 
were  given  on  February  11  and  25,  and  March  11  and  27, 
each  of  0-001  milligramme.  The  patient  gained  1  stone 
6  pounds  in  weight,  and  the  condition  on  discharge  was  a 
thickened  pleura,  with  a  large,  dry  cavity  in  the  lung. 
There  was  no  sputum,  and  only  occasionally  a  dry  cough. 
The  patient  has  continued  well. 

Short1  points  out  that  streptothricial  infection  of  the 
human   subject   is   much   commoner   than   usually   sup- 
posed, and  that  probably  over  2  per  cent,  of  all  cases  of 
perityphlitis  are  due  to  it.     The  disease,   though  very 
1  Lancet,  September  14,  1907,  p.  760. 


214  VACCINE  THERAPY 

chronic,  ends  fatally  in  quite  60  per  cent,  of  the  cases 
within  nine  months.  He  also  describes  a  case  of  actino- 
mycosis  of  the  lungs  in  which  the  signs  were  those  of 
broncho-pneumonia,  except  that  the  dulness  was  uniform. 
The  temperature  was  high,  and  the  result  fatal  within  a 
few  weeks. 

In  view  of  Wynn's  success  with  vaccine  therapy,  the 
importance  of  making  careful  search  for  granules  and 
mycelia  in  obscure  lung  and  appendicular  cases  is  obvious. 


CHAPTER  XIV 

VACCINE  THERAPY  IN  EYE  DISEASES 

OPHTHALMIC  surgeons  would  probably  be  the  first  to  admit 
that  little  further  progress  in  ophthalmology  is  to  be 
expected  from  surgery  pure  and  simple.  The  prime 
essential  is  increase  of  knowledge  in  the  pathology  of 
such  conditions  as  trachoma,  Mooren's  ulcer,  spring 
catarrh,  and  sympathetic  ophthalmia.  Should  a  bacterial 
origin  be  established  for  these,  treatment  upon  opsonic 
lines  will  hold  out  considerable  promise  of  success. 

The  scope  for  vaccine  therapy  in  diseases  of  the  eye  is 
already  great,  and  is  steadily  increasing.  The  first  essen- 
tial for  its  success  is  accuracy  in  the  determination  of  the 
infecting  organism  or  organisms.  In  cases  of  doubtful 
tuberculosis  the  opsonic  index  does  not  always  help  ;  how 
variable  it  may  be  is  shown  in  Table  XVI.  (see  page  216). 

The  explanation  of  this  is  that  the  tendency  in  bacterial 
diseases  of  the  eye  is  for  the  index  to  be  raised.  In 
tuberculosis,  however,  the  ocular  infection  is  often  com- 
plicated by  chronic  infection  elsewhere,  either  of  the 
glands,  lungs,  or  bones,  which  tends  to  the  production  of  a 
lowered  index.  These  two  factors,  working  in  opposite 
directions,  may  result  in  an  index  within  the  normal 
limits. 

The  discovery  of  Calmette's  ophthalmo-reaction  (p.  102) 
promised  to  be  of  great  service.  Thus  Brunetiere1  has 

1  Gaz.  Hebd.  de  la  Soc.  Mid.  de  Bordeaux,  July  18,  1907. 
215 


216 


VACCINE  THERAPY 


recorded  its  value  in  discriminating  between  interstitial 
keratitis  due  to  syphilis  and  to  the  tubercle  bacillus. 
Anbault  and  Lafon1  obtained  positive  reactions  in  a  case 
of  solitary  tubercle  of  the  choroid,  in  two  of  phlyctenulse, 
in  episcleritis,  in  tubercular  interstitial  keratitis,  and  in 
optic  neuritis  with  a  choroidal  nodule  ;  also  in  four  cases 
of  healed  phlyctenule.  Stephenson2  has  employed  it  in 
over  thirty  cases,  among  which  were  six  cases  in  children 
of  relapsing  ulceration  of  the  cornea.  A  positive  result 

TABLE  XVI. 


Case. 

Nature  of  Case. 

Index. 

1 

Interstitial  keratitis 

2-2 

2 

Phlyctenules 

1-9 

3 

Kerato-iritis  with  mutton-fat  deposits 

1-4 

4 

Choroidal  nodule 

1-25 

5 

Kerato-iritis  with  phlyctenules 

1-1 

6 

Tubercular  cyst  of  iris 

0-87 

7 

Neuro-choroidal  retinitis 

0-8 

8 

Choroidal  tubercle 

0-7 

9 

Interstitial  keratitis 

0-7 

10 

Keratitis  with  glands  in  the  neck 

0-55 

11 

Keratitis  with  cervical  and  abdominal  glands 

0-5 

was  obtained  in  each  case,  though  only  two  of  them 
showed  tubercular  lesions  elsewhere.  In  one  case  of 
recent  phlyctenular  keratitis  the  result  was  negative.  In 
three  cases  of  choroiditis  hi  young  women,  free,  appar- 
ently, from  traces  of  syphilis,  the  reaction  was  positive, 
though  no  tuberculous  focus  could  be  found  elsewhere. 
Of  eight  cases  of  interstitial  keratitis,  five  showed  obvious 
signs  of  inherited  syphilis,  and  in  these  the  result  was 
negative  ;  in  the  three  others  it  was  positive. 

1  Gaz.  Hebd.  de  la  Soc.  Mid.  de  Bordeaux,  July  18,  1907. 

2  British  Medical  Journal,  October  19,  1907,  p.  1038 


VACCINE  THERAPY  IN  EYE  DISEASES     217 

Of  three  cases  of  episcleritis  one  had  enlarged  cervical, 
axillary,  and  inguinal  glands,  and  the  result  was  positive  ; 
in  the  two  others  it  was  negative. 

One  case  of  tubercle  of  the  iris,  one  of  tubercle  of  the 
cornea,  and  two  of  chronic  irido-cyclitis  also  gave  positive 
results. 

Two  important  considerations,  however,  militate 
against  its  use  in  ophthalmic  surgery.  The  first  is  that 
it  is  a  test  for  the  presence  of  an  active  tuberculous  focus 
anywhere  in  the  body,  and,  inasmuch  as  syphilitic  kera- 
titis  and  tuberculous  adenitis  may  well  be  coexistent, 
positive  result  cannot  be  taken  as  indicating  certain 
ocular  tuberculosis.  The  second  objection  is  that  the  test 
is  now  regarded  as  inapplicable  to  any  but  a  perfectly 
healthy  eye,  and  the  advisability  of  applying  it  to  the 
other  eye  when  one  is  diseased  is  still  a  matter  of  doubt. 
Should  this  be  decided  upon,  it  is  advisable  to  use  a  more 
dilute  tuberculin  than  is  ordinarily  employed.  A  first 
application  may  be  made  of  a  solution  of  1  in  500.  Should 
no  reaction  occur,  a  second  may  be  made  of  double  this 
strength  ;  beyond  this  it  is  hardly  advisable  to  go,  as 
several  cases  of  severe  corneal  ulceration  or  irido-cyclitis 
have  now  been  reported  from  the  use  of  a  1  per  cent, 
solution. 

A  positive  reaction  is  to  be  considered  merely  as  indi- 
cating an  active  tuberculous  focus  somewhere  in  the 
body.  A  negative  reaction  with  a  solution  of  1  in  250  is 
not  to  be  held  as  proving  the  absence  of  tuberculous 
infection,  but  only  as  confirmatory  evidence  of  its 
absence. 

Assuming  the  diagnosis  of  tuberculosis  to  be  established, 
several  questions  of  importance  require  consideration, 
viz.  : 


218  VACCINE  THERAPY 

1.  Is  the  control  of  index  essential  ? 

2.  The  variety  of  tuberculin  to  employ. 

3.  Dosage  and  interval  in  default  of  index  determina- 
tion. 

As  regard  the  first  of  these,  I  am  personally  always  loath 
to  undertake  cases  of  this  nature  without  the  control  of  the 
index,  for  two  reasons  :  Firstly,  the  dosage  is  by  no  means 
easy  to  regulate  from  clinical  symptoms  ;  and,  secondly, 
the  negative  phase  is  often  of  unusual  length,  even  with 
minimal  doses. 

As  regards  the  second  point,  we  are  quite  ignorant  of 
the  variety  of  the  tubercle  bacillus  at  work  in  ocular 
tuberculosis.     Probably  it  is  sometimes  the  one  variety, 
at  another  time  the  other  variety.     This  consideration 
induced  me  to  give  trial  to  the  mixed  T.R.'s  in  equal 
proportions  ;  the  results  in  the  few  cases  hi  which  it  has 
so  far  been  tried  have  been  so  uniformly  better  than 
those  previously  obtained  that  I  now  make  exclusive  use 
of  this  preparation.     Nor  is  this  all ;  certain  cases  there 
are,  such  as  solitary  tubercle  of  the  choroid  or  iris,  where 
toxaemia  is  altogether  absent,  and  the  efforts  need  only  be 
directed  towards  the  destruction  of  the  bacilli  at  the  in- 
fected focus  ;  but  other  cases  there  are,  such  as  severe 
episcleritis,  especially  when  these  are  secondary  to  tuber- 
culosis elsewhere,  in  which  toxaemia  appears  to  play  an 
important   part.     In   these,    therefore,    I   now   combine 
Denys'  tuberculin  in  conjunction  with  the  mixed  human 
and  bovine  T.R.'s,  as  this  preparation  possesses  powerful 
antitoxin-exciting  properties. 

As  regards  the  third  of  the  above  questions,  while  the 
best  results  certainly  cannot  be  obtained  without  '  in- 
dical '  control,  yet  the  following  scheme  of  treatment 
will,  as  a  rule,  secure  a  good  result  : 


VACCINE  THERAPY  IN  EYE  DISEASES     219 

If  toxaemic  symptoms  be  absent,  begin  with  a  dose 
of  0-00001  c.c.  of  mixed  human  and  bovine  T.R.'s  ; 
repeat  in  twenty-one  days  ;  double  the  dose  after  another 
twenty-one  days  ;  and,  if  all  goes  well,  repeat  this  doubled 
dose  in  seventeen  days.  Then  proceed  cautiously, 
guided  by  symptoms,  increasing  the  dosage  and  diminish- 
ing the  intervals  only  very  gradually. 

In  cases  such  as  severe  episcleritis  or  irido-cyclitis, 
combine  with  the  T.R.'s  a  small  quantity  of  Denys' 
tuberculin,  beginning  with  0*00001  c.c.,  and  doubling  this 
amount  at  each  injection.  The  increase  in  dosage  of 
this  tuberculin  is  thus  more  rapid  than  in  the  case  of 
the  T.R.'s. 

With  females  particular  attention  must  be  paid  to  the 
menstrual  periods,  and  no  inoculation  should  be  per- 
formed within  the  space  of  time  from  three  days  prior 
to  the  onset  of  a  period  to  three  days  after  its  cessation. 

If  treatment  upon  these  lines  be  persisted  in,  uniformly 
successful  results  should  be  secured,  assuming  the  diag- 
nosis to  have  been  correct.  Prolonged  treatment,  how- 
ever, may  be  necessary. 

Choroidal  nodules  may  be  watched  disappearing  by 
means  of  the  ophthalmoscope  ;  gradually  shrinkage 
occurring  until  nothing  is  seen  but  a  white  scar,  or  total 
absorption  takes  place.  Interstitial  keratitis  should  clear 
completely,  and  mutton-fat  deposits  disappear. 


CONJUNCTIVITIS. 

The  forms  of  conjunctivitis  to  which  vaccine  therapy 
is  especially  applicable  are  : 

1.  Acute  forms  :  Gonococcal,  pneumococcal,  strepto- 
coccal. 


220  VACCINE  THERAPY 

2.  Chronic  forms  :  Those  due  to  the  Morax-Axenfeld, 
the  tubercle  and  Friedlander's  bacillus. 

In  the  acute  forms,  vaccine  therapy  is  of  especial 
service,  hi  that  extension  to  other  parts  can  almost  cer- 
tainly be  obviated  if  the  case  be  seen  early.  In  each  of 
these  infections  a  250.000.000  dose  of  stock  vaccine 
should  be  given  as  soon  as  the  organism  has  been  diag- 
nosed from  smears.  Clinical  signs  are  a  quite  sufficient 
guide  to  repetition,  which  may  be  performed  in  three  or 
four  days,  best  with  a  vaccine  meanwhile  prepared  from 
the  patient's  own  organisms.  Such  a  case  was  one  under 
Professor  McHardy.  It  was  seen  by  three  members  of 
the  staff  at  the  Royal  Eye  Hospital,  and  so  bad  a  prog- 
nosis given  that  as  a  last  resort  I  decided  to  give  an 
immediate  inoculation  ;  250,000,000  of  a  stock  gono- 
coccal  vaccine  were  given,  and  the  index  found  to  be 
2*5.  Although  the  patient  was  extremely  negligent  of 
himself,  and  could  not  be  induced  to  use  a  lotion  or  guard 
to  the  other  eye,  improvement  began  immediately,  and, 
despite  the  fact  that  on  the  fourth  day  the  negative 
phase  was  still  persisting,  the  index  being  only  T26, 
marked  change  was  evident.  The  active  process  was 
checked,  there  was  much  less  chemosis  and  little  dis- 
charge. Upon  the  eighth  day  the  index  was  3-8,  and 
the  condition  of  the  eye  so  satisfactory  that  the  patient 
could  not  be  induced  to  make  any  further  attendance. 

Three  cases  of  acute  pneumococcal  conjunctivitis, 
progressing  to  hypopyon  ulcer,  have  also  been  subjected 
by  the  author  to  vaccine  therapy  within  the  past  few 
months.  Two  of  these  cases  were  under  the  care  of 
Dr.  Willoughby  Lyle,  who  has  very  kindly  furnished  the 
following  notes  upon  them  : 

'  A  male,  aged  forty -nine,  was  suffering  from  a  rapidly 


VACCINE  THERAPY  IN  EYE  DISEASES     221 

infiltrating  corneal  ulcer,  with  hypopyon  two-thirds  up 
the  aqueous  chamber.  Local  treatment  was  persevered 
with  for  twelve  days  without  any  improvement  whatever 
taking  place  ;  in  fact,  the  intra-ocular  tension  was  raised 
and  the  local  pain  so  great  (and  there  was  no  per- 
ception of  light)  that  it  was  almost  decided  to  excise  the 
eyeball.  Vaccine  therapy,  however,  was  commenced, 
and  local  treatment  persevered  with.  In  four  days  the 
hypopyon  began  to  disappear,  and  the  cornea  to  clear 
at  the  margins.  From  that  time  until  the  patient  left 
the  hospital — four  weeks  later — the  eye  gradually  im- 
proved. Altogether  two  injections  of  250,000,000,  and 
one  of  500,000,000  pneumococci  were  given.  On  exam- 
ination two  days  after  leaving  the  hospital,  the  local 
condition  was  as  follows  :  There  was  a  large  irregular 
leukomatous  patch,  somewhat  vascular,  over  the  lower 
two-thirds  of  the  cornea,  a  narrow  ring  of  clearer  cornea 
below  the  leukoma.  The  margin  of  the  pupil  could  just 
be  seen  over  the  nebulous  cornea  above.  The  intra- 
ocular tension  was  normal,  and  the  patient  could  distin- 
guish between  light  and  darkness. 

'  The  second  case  was  in  a  child,  aged  three  years  seven 
months,  who  was  admitted  into  the  hospital  with  a 
central  corneal  ulcer  with  infiltrating  margins  and  a 
small  hypopyon.  In  spite  of  local  treatment,  the 
hypopyon  increased,  the  ulcer  spread,  and  the  cornea 
ruptured.  Vaccine  treatment  was  commenced  with  a 
dose  of  175,000,000  pneumococci,  and  from  that  time  the 
eye  began  to  clear.  When  the  child  left  the  hospital  there 
was  a  large  "  leukoma  adherens  ";  the  cornea  was  somewhat 
vascular ;  there  was  a  well-formed  aqueous  chamber  ; 
the  iris  was  a  good  colour,  and  reacted  readily  to  light. 

'  The  favourable  result  obtained  in  these  cases  was 


•2-2-2  VACCINE  THERAPY 

very  largely  due  to  the  vaccine  treatment,  and  but  for 
it  the  first-mentioned  patient  would  undoubtedly  have 
lost  his  eye.' 

The  third  case  was  under  the  care  of  Mr.  L.  V.  Cargill. 
and  was  a  very  severe  one.  As  soon  as  the  pneumo- 
coccus  was  isolated,  a  dose  of  250,000,000  of  the  pneumo- 
coccal  vaccine  which  had  been  prepared  for  Case  1  of 
Dr.  Lyle's  was  given.  Improvement  began  within 
twenty-four  hours,  and  progressed  with  extreme  rapidity. 
The  hypopyon  was  rapidly  absorbed,  and  the  patient 
discharged  within  a  week. 

Of  the  three  forms  of  chronic  conjunctivitis,  two  are, 
it  is  true,  uncommon,  but  are  singularly  intractable  to 
ordinary  treatment.  I  refer  to  the  forms  due  to  the 
tubercle  bacillus  and  the  bacillus  of  Friedlander.  The 
latter  of  these  is  especially  intractable,  and  may  persist 
for  years  ;  whereas  improvement  may  be  anticipated 
from  the  administration  of  a  single  dose  of  250,000,000 
organisms,  and  cure  from  three  or  four  doses.  The  third 
form,  by  far  the  commonest  variety  of  chronic  con- 
junctivitis, is  that  due  to  the  Bacillus  lacunaius  of 
Morax-Axenfeld,  and  occasionally  proves  very  resistant 
to  treatment,  especially  in  old  people.  Such  cases  should 
receive  two  or  three  injections  of  100,000,000  organisms 
at  intervals  of  two  or  three  weeks,  clinical  appearances 
being  sufficient  guide  as  to  the  appropriate  time  for 
repeating  the  injection.  Should  cure  not  result,  one  or 
two  doses  of  250,000,000  organisms  will  almost  certainly 
achieve  this  end.  This  organism,  though  easy  to  isolate, 
yields  but  feeble  growth,  and  the  preparation  of  the 
vaccine  is  no  easy  matter.  The  results  are,  however,  so 
satisfactory  as  to  afford  sufficient  compensation  for  the 
trouble  and  expense  incurred. 


VACCINE  THERAPY  IN  EYE  DISEASES     223 

CORNEAL  ULCERS. 

The  bacteriology  of  these  is  not  well  known.  The 
tubercle  bacillus  and  pneumococcus  are  certain  causes 
of  some  chronic  varieties.  Acute  ulceration  may  be  due 
to  streptococcus,  staphylococcus,  gonococcus,  Bacillus 
coli  communis,  Bacillus  pyocyaneus,  and  other  organisms. 
No  matter  how  high  the  index  may  be  to  an  infecting 
organism  in  these  cases,  immediate  injection  of  a  stock 
vaccine  should  be  made  as  soon  as  the  infection  has  been 
identified.  The  preparation  of  a  vaccine  from  the  patient's 
own  bacteria  should  then  be  proceeded  with,  and  a  fresh 
injection  be  given  should  no  response  to  the  stock  vaccine 
be  noticeable. 

Of  the  chronic  forms  due  to  the  pneumococcus,  the 
ulcus  serpens  corneae  is  the  best  known.  Two  such  cases 
have  been  treated  by  the  author,  with  complete  success 
by  means  of  autogenous  vaccine.  One  of  these  deserves 
further  mention.  The  patient  was  a  man,  eighty  years 
of  age,  under  the  care  of  Mr.  Brookbanks  James,  and 
was  admitted  with  a  very  bad  corneal  ulcer.  A  large 
hypopyon  was  present  ;  the  cornea  was  very  opaque,  the 
iris  bound  down  by  adhesions,  and  the  tension  +  1'5. 
Cauterization,  paracentesis,  and,  later,  sclerotomy  for 
the  relief  of  tension  and  evacuation  of  the  hypopyon, 
brought  only  temporary  improvement,  and  excision 
seemed  the  only  remedy.  The  condition  was  still  acute 
when  the  pneumococcus  was  isolated  and  a  vaccine 
prepared.  Despite  the  high  index  to  this  organism — 
viz.,  2-5 — an  injection  of  250,000,000  organisms  was 
given.  Within  three  days  the  eye  began  to  improve 
in  appearance  ;  at  the  end  of  a  week  the  index  was  4-2, 
and  after  a  fortnight  3-0.  A  second  injection  was  then 


224  VACCINE  THERAPY 

given,  with  the  result  that  eighteen  days  later  the 
index  stood  at  6*3,  and  the  inflammation  had  quite 
subsided.  A  large  partial  staphyloma  of  the  cornea  which 
developed  later  was  treated  radically  by  excision 
without  the  use  of  sutures.  No  reaction  followed  the 
operation,  and  the  final  result  was  an  eye  in  which 
some  slight  vision  was  preserved,  and  a  firm  flat  scar 
in  the  cornea  left  in  the  site  of  the  staphyloma.  Several 
months  later  the  eye  was  quite  quiet  and  free  from 
irritability. 

The  following  case  of  ulcerative  keratitis,  under  the  care 
of  Professor  McHardy,  at  the  Royal  Eye  Hospital,  is  not 
without  interest  :  The  patient  had  already  had  one  eye 
removed  for  chronic  ulcerative  keratitis,  going  on  to  per- 
foration, shrinking  of  the  globe,  and  considerable  pain. 
About  eighteen  months  subsequently  the  second  eye  was 
also  attacked  ;  general  superficial  erosion  of  the  cornea 
went  on  to  infiltration  of  the  more  superficial,  then  of  the 
deeper  layers  of  the  cornea  ;  the  tension  fell  considerably 
and  vision  was  practically  nil,  only  dim  perception  of  light 
being  possible.  Cultures  from  the  surface  of  the  globe 
yielded  large  cocci  not  staining  by  Gram's  method,  which 
were  apparently  not  the  Micrococcus  catarrhalis,  and  diplo- 
cocci  which  morphologically  resembled  the  pneumococcus, 
but  could  not  be  isolated.  Upon  the  chance  of  the  infec- 
tion being  a  pneumococcal  one,  two  injections  of  a  vaccine 
were  given  without  producing  any  good  result  ;  on  the 
contrary,  the  condition  became  rather  worse.  The  vision 
was  so  bad  that  an  iridectomy  was  decided  on.  The  iris, 
when  seized  by  the  forceps,  simply  tore  at  once,  it  was  so 
pulpy  ;  cultures  were  made  from  this  small  portion  of 
iris  and  from  scrapings  of  an  eroded  portion  of  the  cornea, 
and  the  same  non-Gram-staining  coccus  obtained  from 


VACCINE  THERAPY  IN  EYE  DISEASES     225 

both.  The  organism  so  far  has  not  been  identified,  but  a 
vaccine  was  made  of  it  as  a  last  hope.  A  first  injection  of 
250,000,000  organisms,  the  index  being  0-5,  was  followed, 
ten  days  later,  when  the  index  was  0-8,  by  a  second  of 
like  amount  ;  seventeen  days  after  the  first  injection,  the 
index  being  1-5,  the  eye  began  definitely  to  improve,  and 
steadily  continued  to  do  so.  Twenty-eight  days  after 
the  second  injection  the  index  was  2-6,  and  a  further 
dose  of  400,000,000  given.  The  eye  was  now  very 
much  better  ;  vision  was  returning,  fingers  being  seen  at 
about  1  foot.  In  another  twenty-six  days  the  patient 
could  discern  faces  fairly  well,  and  a  further  injection  of 
500,000,000  cocci  was  given.  A  fortnight  later  vision 
was  further  improved,  and  the  patient  was  discharged. 
When  seen  two  months  later,  vision,  both  near  and  for 
distance  =  75^  ;  the  cornea  was  diffusely  nebulous;  the 
eye  was  quite  quiet,  and  vision  had  decidedly  improved 
since  the  patient  had  left  the  hospital. 

Mackay  described  before  the  Ophthalmological  Society 
a  case  of  phlyctenular  keratitis.  Tubercle  bacilli  could 
not  be  found,  and  the  tuberculo-opsonic  index  was  within 
normal  limits.  The  staphylococcal  index  being  1-24. 
treatment  with  this  vaccine  was  begun ;  improve- 
ment began  immediately,  but  recurrences  occurred 
when  too  long  intervals  were  left  between  the  inocula- 
tions. 

The  patient  has  remained  well  since  completion  of  the 
treatment. 

Brief  reference  may  finally  be  made  to  the  assistance 
afforded  the  surgeon  hi  such  conditions  as  recurrent 
'  hordeolum  '  and  meibomians,  for  which  staphylococci 
are  responsible,  and  in  chronic  dacryocystitis,  which,  as 
Eyre  has  shown,  is  practically  always  due  to  the  Strepto- 

15 


226  VACCINE  THERAPY 

coccus  pyogenes  longus,  whether  subsequent  to  acute 
streptococcal  conjunctivitis  or  to  one  of  the  other  acute 
forms  ;  in  this  instance  doses  of  100,000,000  organisms 
may  be  begun  with,  and  repeated  or  increased  at  intervals, 
best  controlled  by  determinations  of  the  index  or,  in 
default  of  these,  by  the  clinical  appearances. 


APPENDIX 

I.  OPSONIC  INDEX,  DETERMINATION  OF,  TOWARDS 
SPECIAL  ORGANISMS— PRACTICAL  HINTS 

1.  WHATEVER  the  organism,  use  plenty  of  culture  ;  make 
a  very  thick  emulsion  ;  centrifuge  well ;  pipette  off  upper 
layers  ;  dilute  and  centrifuge  again  ;  dilute  down  upper 
layers  to  required  density,  which  can  only  be  judged  by 
experience. 

2.  In   tubercle   determinations   never   use   a   dried-up 
culture  or  powder  ;  either  preserve  a  growth,  which  has 
been  proved  to  stain  well,  as  a  moist  magma,  killing  by 
exposure  to  direct  sunlight  for  twelve  to   twenty-four 
hours,  or  use  a  living  culture  and  treat  as  above  (1), 
making  up  the  emulsion  with  1-5  per  cent,  salt  solution  to 
avoid  spontaneous  phagocytosis. 

3.  The  meningococcus  and  Bacillus  coli  communis  are 
but   slightly   susceptible   to   phagocytosis   when   freshly 
isolated,  especially  by  normal  sera  ;  hence  for  diagnostic 
purposes  it  is  well  to  employ  a  growth  which  has  been 
repeatedly  subcultured  (ten  to  twenty  times).     In  addi- 
tion to  these  organisms,  the  Bacillus  typhosus,  Micrococcus 
melitensis,  tubercle  bacillus,  and  meningococcus  are  very 
apt  to  be  agglutinated  by  '  immune  '  sera.     It  is  therefore 
well  to  employ  a  strain  which  has  lost  this  property, 
bearing  in  mind,  however,  that  the  true  opsonic  power 
of  the  patient's  serum  to  his  own  organisms  has  not 
thereby  been  determined. 

227  15 — 2 


228  VACCINE  THERAPY 

4.  In  determining  indices  to  the  Bacillus  typhosus  and 
Bacillus  dysenteries,  Semple  advises  the  following  method  : 
Dilute  the  serum  1  in  5  ;  then  heat  it  for  fifteen  minutes  at 
58°  C.,  and  take  2  volumes  of  heated  and  diluted  serum, 
2  volumes  of  washed  blood-cells,  and  1  volume  of  typhoid 
emulsion.  Incubate  for  fifteen  minutes  at  37°  C.  ;  make 
films,  and  stain  with  Leishman's  stain  ;  then  with  0- 1  per 
cent,  methylene  blue  for  one  minute  to  bring  out  the  bac- 
teria more  clearly.  By  this  procedure  the  bactericidal 
properties  of  the  serum  and  the  thermolabile  opsonins  are 
both  done  away  with. 

II.  THE  TUBERCLE  BACILLUS. 
A.  Special  Methods  for  its  Detection  from  Various  Sources. 

1  The  Sputum. — When  the  bacilli  exist  in  but  scanty 
numbers,  either  of  the  following  methods  will  prove 
useful  :  Digest  the  sputum  for  twenty-four  to  forty- 
eight  hours  in  the  incubator  with  either  pancreatic 
extract  or  with  pepsin  ;  centrifuge  and  examine  the 
deposit.  Or  dilute  the  sputum  with  twenty  times  its 
volume  of  water,  stir  well,  add  a  little  dilute  acetic  acid 
to  precipitate  mucin  and  nucleo-albumin,  filter,  centri- 
fuge thoroughly,  and  examine  the  deposit. 

2.  The  Fceces. — Strassburger  advises  that  a  small 
particle  be  rubbed  up  with  water,  and  centrifugalized 
for  a  very  short  time  to  throw  down  the  large  particles. 
The  fluid,  which  holds  the  bacilli  in  suspension,  is  poured 
off  and  diluted  with  twice  its  volume  of  methylated  spirit. 
This  so  reduces  the  specific  gravity  that  the  separation 
of  the  bacilli  by  the  centrifuge  is  rendered  quite  easy. 

Nabra's  method  is  as  follows  :  Place  a  small  portion 
in  a  porcelain  dish  ;  dilute  with  alcohol  at  40°  C.  until 


APPENDIX  229 

complete  disintegration  has  occurred  ;  add  a  little  ether, 
and  stir  thoroughly ;  allow  to  stand  until  the  ether 
evaporates  and  a  scum  forms.  This  latter  will  contain 
all  the  microbial  elements. 

Rosenberger  1  examined  the  stools  of  672  patients,  in 
60  of  whom  tuberculous  infection  had  been  diagnosed. 
Tubercle  bacilli  were  found  in  120,  or  19-6  per  cent.,  of  the 
cases  in  which  the  diagnosis  of  tuberculosis  had  not  been 
made,  and  in  all  the  tuberculous  cases.  No  acid-fast 
bacilli  other  than  tubercle  were  found.  In  acute  miliary 
tuberculosis  they  were  always  present,  and  in  well-defined 
cases  of  pulmonary  phthisis.  Hence,  the  presence  of 
tubercle  bacilli  in  the  faeces  does  not  necessarily  denote 
tuberculous  enteritis.  In  all  cases  of  chronic  diarrhoBa 
and  of  general  glandular  enlargement,  search  should  be 
made  in  the  faeces  for  the  tubercle  bacillus. 

3.  The  Urine. — Dilution  with  two  to  three  times  its 
volume  of  methylated  spirit  will  greatly  assist  the  separa- 
tion by  centrifuge  of  the  tubercle  bacilli  from  urine. 

B.  Speedy  Methods  for  the  Isolation  of  the  Tubercle  Bacillus. 

Two  methods  may  be  found  useful.  In  the  first  a 
suitable  lump  of  the  sputum  is  washed  well  in  sterile 
salt  solution.  Four  parts  of  pure  glycerine  are  then 
taken  for  every  one  part  of  sputum,  and  the  mixture 
incubated  at  37°  C.  for  ten  to  fourteen  days.  Slight  cen- 
trifugalization  will  throw  down  the  tubercle  bacilli,  which 
may  be  pipetted  off,  washed  with  sterile  salt  solution,  and 
used  to  inseminate  tubes  of  broth  and  of  nutrose  glycerine 
agar.  A  pure  culture  is  then  usually  obtained  (Williamson). 

In  the  second  method  animal  inoculation  is  employed. 

1  American  Journal  of  Medical  Science,  December,  1907. 


230  VACCINE  THERAPY 

A  guinea-pig  is  taken,  and  its  lumbar  glands  forcibly 
massaged.  The  inoculum  is  then  introduced  in  the 
ordinary  way,  and  the  glands  again  massaged  in  a  day 
or  two.  This  has  been  found  so  greatly  to  increase  their 
liability  to  infection  that  cultures  may  usually  be  ob- 
tained from  them  within  a  fortnight,  instead  of  four  to 
six  weeks. 

C.  Special  Staining  Methods  for  the  Tubercle  Bacillus, 
with  a  View  to  the  Differentiation  of  the  Human 
and  Bovine  Varieties. 

Spengler l  has  paid  particular  attention  to  this  question. 
He  lays  especial  stress  on  two  points  :  (1)  The  necessity 
for  making  a  thin  homogeneous  smear  fairly  representa- 
tive of  the  whole  secretion  ;  (2)  the  extreme  importance 
of  avoiding  overheating,  as  this  will  destroy  the  envelope 
of  the  bacillus,  which  is  composed  of  wax  of  a  low  melting- 
point.  A  thin  film  is  made,  and  aUowed  to  dry  in  the 
air.  It  is  then  dipped  into  1  per  cent,  caustic  soda 
solution  and  dried  by  most  careful  warming.  The 
preparation  is  then  covered  with  Loffler's  methylene-blue, 
to  give  a  ground  colour  to  the  envelope  of  the  bovine 
bacillus  (the  envelope  of  the  human  variety  is  not  thereby 
stained).  It  is  then  washed  with  water  and  stained 
with  warm  carbol-fuchsin,  which  is  allowed  to  steam 
but  slightly,  and  again  washed  with  water.  It  is  then 
counterstained  for  a  few  seconds  with  methylene-blue, 
to  which  one  or  two  drops  of  15  per  cent,  solution  of 
nitric  acid  are  added.  This  is  then  washed  off  with  water, 
the  slide  dried  between  the  filter-paper,  and  warmed  very 
gently.  '  If  both  human  and  bovine  bacilli  be  present  on 

1  Deut,  Med.  WocJi.,  1907,  No.  9. 


APPENDIX  231 

the  slide,  little  trouble  will  be  found  in  differentiating 
them.  The  bovine  has  a  so  much  thicker  and  sharper 
envelope  than  the  human  that  it  appears  to  be  very 
much  larger  and  thicker  than  the  latter.' 

In  cases  of  tuberculosis  which  are  approaching  cure, 
or  in  whom  the  resistance  is  very  good,  the  bacteria  may 
fail  to  stain  by  ordinary  methods,  and  Spengler  advises 
the  following  procedure  :  Make  a  thin  homogeneous 
smear  as  before  ;  dry  in  the  air,  and  stain  with  warm 
carbol-fuchsin,  avoiding  excessive  heating.  Without 
washing,  add  a  mixture  of  equal  parts  of  absolute  alcohol 
and  of  either  a  saturated  aqueous  solution  of  picric  acid 
or  of  Esbach's  solution,  leaving  this  in  for  two  or  three 
seconds.  Then  add  three  to  four  drops  of  15  per  cent, 
solution  of  nitric  acid,  and  again  picric  acid  alcohol  for 
five  to  ten  seconds,  until  the  smear  is  of  a  light  yellow 
colour.  Wash  with  distilled  water,  dry  carefully,  wash 
with  60  per  cent,  alcohol  ;  then  for  a  few  seconds  with 
15  per  cent,  nitric  acid  till  a  light  yellow  ;  again  with 
60  per  cent,  alcohol.  Finally,  contrast  stain  with  picric 
acid  alcohol  until  the  smear  is  well  coloured ;  wash  with 
distilled  water  ;  dry  and  mount. 

By  means  of  these  special  methods,  Spengler,1  has 
succeeded  in  demonstrating  certain  bodies  which  stain 
the  same  as  the  tubercle  bacillus,  and  appear  as  though 
they  might  be  cross-sections  of  bacilli.  He  now  considers 
these  bodies  as  true  spores  when  of  the  bovine  variety 
(being  more  resistant  to  heat  than  the  bacilli),  and  as 
*  sporoids  '  when  of  the  human  type  (being  then  less 
resistant).  They  sometimes  appear  as  single  bodies,  but 
are  often  found  in  masses.  These  spore-forms  especially 
occur  when  the  culture  medium  is  poor.  They  may  be 
1  Zeitschrift  f.  Hyg.  u.  Infect.  KranJc.,  Bd.  xlix.,  1905. 


232 


VACCINE  THERAPY 


inoculated  in  good  media  and  made  to  produce  full-sized 
bacilli.  They  are  found  most  plentifully  in  patients  with 
good  resisting  power,  because  their  tissues  offer  a  poor 
culture  medium.  Spengler  has  often  found  these  forms 
in  the  fseces  in  cases  of  intestinal  tuberculosis,  and  in  the 
blood  in  cases  of  acute  miliary  tuberculosis.  To  demon- 
strate these  '  Splitter '  forms,  the  first  of  the  above 
methods  is  the  better. 


D.  The  Index  to  both  Human  and  Bovine  Types  in  Cases 
of  Pulmonary  Tuberculosis,  and  the  Effect  of  Injec- 
tions of  the  Two  Varieties  of  T.R. 

The  index  in  pulmonary  tuberculosis  to  the  human  and 
bovine  types  respectively,  and  the  effect  thereupon  of 
injections  of  the  two  T.R.'s,  has  been  investigated  in  a 
number  of  cases  by  Williamson,  who  has  kindly  supplied 
me  with  the  following  charts  (Nos.  XVII. -XXI.)  : 

CHART  XVII. 


9 
8 
•7 

•6 

•r. 

-1-0 

,"•• 

-\ 

f 

• 

^J 

rs~ 

•  < 

_._. 

-•— 

-* 

9' 
\ 

/ 

fx 

\ 

s 

/^ 

V 

X 

^ 

T 

^ 

• 

—  ^ 

•' 

*v- 

-—  • 

-•*' 

Index  determined  morning  and  evening,   patient  resting  in  bed.     Dotted 
line  =  index  to  bovine  type  ;  continuous  line  =  index  to  human  type. 

Chart  No.  XVII.  is  a  typical  one  of  six  cases.  The 
sputum  contained  abundant  tubercle  bacilli,  and  the 
patient  rested  in  bed  during  the  estimations.  It  will  be  seen 
that  the  indices  to  the  human  and  bovine  types  respec- 
tively moved  in  inverse  directions  ;  when  the  index  to  the 
human  type  rose,  that  to  the  bovine  fell,  and  vice  versa. 


APPENDIX 


233 


Chart  No.  XVIII.  exhibits  similar  features.  Tubercle 
bacilli  were  numerous,  and,  according  to  Spengler's 
methods  of  staining,  both  types  appeared  to  be  present. 
It  will  be  observed  that,  although  the  index  to  the  bovine 
type  rose  from  0-6  to  0-94,  that  to  the  human  fell  from 


1-0 
•9 
8 
•7 
•6 

.4 

CHART  XVIII. 

MEMEMEMEMEMEMEMEMEUEM 

y^ 

^ 

,.»•- 

-•^ 

l*>1 

s 

*\ 

X 

,«'- 

,jir~ 

>».-, 

«•-. 

-*" 

\fc 

-_  ~- 

^.. 

--••' 

_-»•- 

-•*•' 

*~ 

—  ••- 

—  ••* 

< 

-•*•' 

s 

X 

s- 

-*** 

**- 

• 

—  ^ 

~J2. 

s** 

^ 

s+- 

-V 

'V 

^iS 

IE 

^ 

Index  determined  morning  and  evening,  patient  in  bed ;  heavy  lung  exercises. 
Patient  gained  13  Ibs.  in  weight.     Lines  indicate  as  before. 

1-0  to  0-6;  despite  this,  the  patient  did  very  well,  and 
gained  13  pounds  in  weight.  The  more  important  of  the 
two  infections  would  therefore  appear  to  have  been  the 
bovine  one. 

That  the  indices  to  the  two  types  do  not  always  move 
in  opposite  directions  is  seen  in  Chart  No.  XIX.      The 


Day 
1-3 
•2 
•1 
1-Q 
•9 
•8 
.1 

CHART  XIX. 
; 

1       2       3      4       5       6      7       8      9       10     11       12      13     14      15      16      17      18      19     20     21 

«., 

<^"*- 

_,^" 

-0- 

"*•, 

r-»S 

_ 

K 

'••••" 

"•v' 

"*" 

"••^r- 

"" 

1 

"*••" 

"*«••- 

—  *.. 

? 

i 

^A 

» 

^S 

^~ 

—  1  — 

—  *s 

s~ 

~*\ 

§ 

rea/ 

in 

bed 

/ 

X' 

hv 

/ 

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1 

S~~ 

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V 

** 

Daily  determinations  of  index.  Few  tubercle  bacilli  in  sputum.  Tempera- 
ture normal  morning  and  evening  upon  graduated  exercises.  Upon  the 
twelfth  day  developed  a  pleuritic  pain,  and  was  accordingly  in  bed  till  the 
sixteenth  day.  High  index  to  the  human  strain  upon  the  seventeenth  day 
confirmed  by  a  duplicate  estimation. 

onset  of  a  slight  pleuritic  attack  raised  the  index  to  the 
human   type  from  0-8  to   1-2,  without  influencing  that 


234 


VACCINE  THERAPY 


to  the  bovine  type  to  anything  but  a  slight  extent  ;  the 
tendency  is,  however,  there. 

The  effect  of  injection  of  a  human  T.R.  upon  the 
index  to  the  human  bacillus  has  been  fully  described  in 
the  text ;  the  effect  upon  the  index  to  the  bovine  bacillus 
requires  further  elucidation. 

From  Chart  No.  XX.  it  will  be  seen  that  an  injection  of 
0-00001  c.c.  of  bovine  T.R.  had  no  effect  upon  the  index 


MEM 


CHART  XX. 

E       M       E       M       E       M       E 


M       E 


Case  of  Very  Advanced  Phthisis,  with  Moderate  Inverse  Pyrexia.—0\rmg, 
perhaps,  to  advanced  state  of  disease,  immunizing  response  to  injections  poor. 
The  indices  point  to  bovine  nature  of  infection. 

to  the  human  type  in  a  case  of  advanced  phthisis,  whereas 
it  produced  a  definite  but  slight  rise  in  the  index  to  the 
bovine  type. 

Chart  No.  XXI.  shows  very  well  the  effects  of  injection 
of  the 'mixed  T.R.'s  as  advocated  by  the  author  during  the 
past  year.  It  will  be  seen  that  the  indices  to  both  types 
rose  most  satisfactorily.  The  dosage  of  the  T.R.'s  given 
was  so  small  that  no  effect  was  produced  upon  the  tem- 
perature ;  the  moist  sounds  were,  however,  multiplied, 
and  the  character  of  the  sputum  altered. 

These  charts  are  only  typical  of  many,  and  the  work 
is  to  be  continued  ;  but.  so  far  as  it  goes,  it  appears  to 


APPENDIX 


235 


justify  the  author's  contention  that  the  human  T.R. 
raises  the  index  to  the  human  bacillus,  and  only  slightly 
affects  that  to  the  bovine  bacillus,  and  vice  versa  ;  while 
an  injection  of  the  mixed  T.R.'s  causes  elevation  of  the 

CHART  XXI. 

To  SHOW  EFFECT  OF  INJECTION  OF  MIXED  T.R.'s  UPON  THE  INDICES 

TO  THE  Two  STRAINS. 
Days 

I        2       34       567       6       0       10       II       12      13      14      15      16      17      18      18      20    21 


A-. 

t 

—  s 

», 

i 

' 

1 

•"*•- 

—»- 

«  _ 

^ 

"*•' 

1 

""• 

/ 

's 

•^ 

/ 

5 

s 

/ 

/ 

\ 

^v 

r* 

-•\ 

\ 

S 

/ 

\ 

*N 

/ 

, 

/ 

\ 

J 

\ 

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\— 

--*-. 

—  *.x 

/ 

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V^ 

V 

^— 

*4 

i 

Case  of  Early  Phthisis.— Upon  the  eighth  day  0 "00001  c.c.  of  each  T.R. 
(human  and  bovine)  were  given.  The  effect  upon  the  indices  is  seen  in  the 
chart.  The  temperature  remained  normal,  the  moist  sounds  were  multiplied, 
and  the  sputum  became  slightly  blood-stained. 

index  to  both  :  so  that,  if  opsonin  be  the  important  im- 
munizing factor  in  tuberculosis,  the  mixed  T.R.'s  should 
be  employed  in  all  cases  where  the  exact  nature  of  the 
infecting  organism  has  not  been  determined. 


Acne      ...  -     150 

„     dosage  of  staphylococcus  vaccine            -             -  -             -     151 

,,     indurata                             .....  151,  153 

Actinomycosis  :  vaccine  treatment        .....     212 

Addison's  disease  :  diagnosis  by  means  of  opsonic  index  -                    83 

Adenitis  :  diagnosis  of  tubercular  adenitis  by  opsonic  index  -             -       83 

„         dosage  of  tuberculin  .....     139 

,,         types  of  tubercle  bacilli  responsible  for        -  -     138 

tubercular     -                          -  83,  137 

„         use  of  mixed  tuberculins       -             -             -  -             -     1 16 

Administration  of  vaccines        -  -       68 

„               „         „         by  the  mouth        -  -       70 

Anti-opsonins    ...  -       14 

Anti-typhoid  immunization       -  -          198, 202 

„            vaccine     -  -     199 

Bacillus  coryzce  segmentosus.     See  Bacillus  septus. 

Bacillus  coli  communis  :  emulsion  ...  33,  227 

„  „  „  group  of  bacilli  -  -  192 

,,  ,,  „  in  genito-urinary  disease  -  -  147 

,,  ,,  ,,  in  intestinal  disease  -  -  147 

„  „  „  in  septicaemia  -  160 

„  „  „  preparation  of  vaccine  -  -  53 

„  „  „  vaccine  treatment  -  -  193 

,,  „  „  vaccine  dosage  -  196 

Bacillus  of  Friedlander  17,  18,  184,  222 

„  „  „  preparation  of  vaccine  -  54 

„  „  „  vaccine  in  chronic  nasal  catarrh  -  -  190 

„  „  „  vaccine  in  chronic  gleet  -  173 

„  „  ,,  vaccine  in  acute  nasal  catarrh  187,  189 

Bacillus  Morax-Axenfeld :  conjunctivitis  .  -  -  222 

„  „  „  emulsion  -  -  33 

Bacillus  paralyticans     -  -     207 

Bacillus  paratyphosus   ......  192,  196 

Bacillus  septus  ......          182,  185 

„  ,,  differentiation-  -  55 

„  „  effect  of  vaccine  on  opsonic  index  -  -  18 

„  „  preparation  of  vaccine  -  -  54 

236 


INDEX  237 

PAGES 

Bacittus  septus,  use  of  stock  vaccine     -             -  47,  186 

„           „       vaccine  treatment  of  nasal  catarrh  -     188 

Bacillus  typhosus                        -            -  -     196 

„               „       determination  of  opsonic  index  -                          -     227 

Bazin's  disease               ...  .     144 

Blood :  collection  for  estimation  of  opsonic  index  -                          -       30 

Blood-cells  :  preparation  of,  for  opsonic  index  -  -             -             -       31 

Blood-films  :  method  of  spreading        -  34 

Boils      -  -     153 

Bovine  tubercle  :  antagonism  to  human  113,  232 

Calmette's  ophthalmo-reaction    -  102,  215 

Calcium  salts  :  use  of  -  -     126 

Carbuncles         -  -     153 

Caries  of  superior  maxillary  bone  -     143 

Caseation  in  tuberculous  adenitis  -     139 

Catarrh  -     184 

„       bacteriology  of  nasal  catarrh   -  -     184 

„       of  accessory  air  sinuses  ...     185 

tracheal  185,  189 

,,       treatment  of  acute  catarrh  of  respiratory  passages       -  186 

,,       treatment  of  chronic  nasal  catarrh      -  -     190 

Catarrhalis,  M.     See  Micrococcus  catarrhalis. 

Cholecystitis :  vaccine  treatment                         ...  193, 202 

Chorea :  Streptococcus  rheumaticus        -  -     164 

Choroiditis          -  -     216 

Clumps  in  opsonic  slides  -       37 

Colds  :  effect  on  opsonic  index  17,  186 
Colon  bacillus.     See  Bacillus  coli  communis. 

Combined  vaccines  :   in  acute  catarrh  -             -     187 

„             „             in  chronic  gleet  -  ...     173 

,,             ,,             in  empyemata     -  -     171 

„             ,,             in  septicaemia      -  -     161 

,,             ,,             in  tracheal  catarrh  -     190 

,,             „             preparation  -       66 

Conjunctivitis  :  chronic  -     222 

gonoccocal        -  -      21, 46, 220 

,,              pneumococcal  and  strep tococcal  -             -     220 

Corneal  ulcer     -                         -  -             -     223 

Counting  opsonic  slides  37,  41 

Cumulative  phases         -  -       24 

Cystitis  -       84 

Dacryocystitis  :  chronic  -     225 

Denys'  tuberculin  - 117,  124,  130 

Diagnosis  by  Calmette's  reaction         -  -                          -     102 

,,         by  means  of  the  opsonic  index      ....     104 

,,         by  means  of  the  opsonic  index  during  menstruation  -       87 

,,          by  opsonic  index  of  gonococcal  infection      -  -     172 

,,          by  opsonic  index  with  diluted  sera  -  -       88 


238  INDEX 

PAGES 

Diagnosis  by  the  old  tuberculin  test    -  ...       99 

„         by  Von  Pirquet's  reaction   -  ...     102 

„         of  tuberculous  infection       -  -             -       99 

Dtiuteet'sera  in  estimation  of  opsonic  index       -  -             -             -42 

Diplococcus  intracellularis  (Weichselbaum).     See  Meningococcus. 

Dosage  of  anti-typhoid  vaccine  -             -     199 

„       of  Bacillus  coli  comrnunis  vaccine  -             -     196 

„       of  meningococcus  vaccine         -  -             -     212 

in  corneal  ulcers  -  223,  225,  226 

„       of  Denys'  tuberculin     -  -          124,  130 

„       in  eye  diseases  -          219,  222 

,,       of  Forster's  vaccine  in  dysentery  -             -     204 

,,       of  gonococcal  vaccine   -  -                       177,  182 

„       in  gonorrhoeal  arthritis  -             -     178 

„       in  gonorrhceal  vulvo-vaginitis  -  -             -     180 

„       of  pneumococcal  vaccine  -             -             -     168 

in  Malta  fever  ....     206 

„       of  Spengler's  P.T.O.      -  -     124 

,,       of  staphylococcal  vaccine  in  acne  -     151 

,,       of  staphylococcal  vaccine  in  septicaemia  and  pyaemia    -  -     156 

,,       of  streptococcal  vaccine  in  septicaemia  -     162 

„       of  tuberculin :  theory   -  -       21, 23, 25 

,,       of  tuberculin :  initial  dose        -  -             -     127 

„       of  tuberculin :  T.A.  (old  tuberculin  Koch)  -                          -     122 

of  tuberculin  :  T.R.  and  P.T.R.  -     125 

of  tuberculin  :  B.E.  (human)  and  P.B.E.  (bovine)        -  -     126 

,,       of  mixed  tuberculins    -  -     130 

„       of  tuberculin  with  guidance  of  opsonic  index  -                          -     129 

,,       of  tuberculin  in  tuberculous  adenitis    -  -     139 

,,       of  tuberculin  (Turton's)  -     135 

„       in  tracheal  catarrh        -  -     190 

Dysentery  -     202 

,,         treatment  with  vaccines      -  -     204 

Empyema :  treatment  with  streptococcal  vaccine  -                          -     162 

Emulsion  :  preparation  for  opsonic  index         -  33, 227 

„           preparation  for  vaccines     -  -                          -       58 

Endocarditis  :  diagnosis  by  means  of  opsonic  index  -                           -       83 

Endometritis  :  diagnosis  by  means  of  opsonic  index  -             -             -       84 

Enteric  fever  :  treatment  -             -     201 

Epididymor  chilis  :  diagnosis  by  means  of  opsonic  index  -       84 

Episderitis         -  -     219 

Erysipelas  :  streptococcal  -     162 

Exercise  :  effect  on  opsonic  index        -  -       71 

Eye  :  vaccine  therapy  in  eye  disease    -  -     215 
,,      tuberculous.     See  Ocular  tuberculosis. 

Furunculosis      -  -     153 

Genito-urinary  tuberculosis        -  -     145 

Gonococcus         -             -            -             -         .  -  -            -            -173 


INDEX  239 

PAGES 

Gonococcus  emulsion      -  -       33 

,,           medium  for  growth                           -  -       47 

,,           method  of  obtaining  culture           -             -  -       51 

„           preparation  of  vaccine        -                          -  51 

vaccine        -                                                    -  -  46,  177,  182 

Gonorrhoea :  acute         -  -     178 

chronic      -  -       172,  173,  175,  176 

„           chronic  :  treatment  with  lactic  acid  bacilli  -             -     177 

,,           dosage  of  vaccine              -                          -  177,  182 

,,           importance  of  opsonic  index  in  treatment  -             -     182 

,,           treatment                                                      -  -             -     177 

,,           use  of  stock  vaccines         ...  -       46 

Gonorrhceal  arthritis      •  •          178,  179 

,,          conjunctivitis  46, 220 

,,           vulvo-vaginitis        -  -             -     180 

Graduated  exercise  in  treatment  of  tuberculosis  -     128 

Hcemophagocytic  index :  method  -             -             -             -       43 

Hordeolum         -            -  ....     225 

Human  tuberculin,  T.B.             -  ...     138 

Human  type  of  tubercle  -             -             -             -             -113 

Infection  with  tubercle  -  96 

Inoculation  of  vaccines               -             -             -  -             -                    68 

Insane  :  opsonic  index  in  the  -  80 

Intestinal  tuberculosis   -             -            -            .  ,         .             .             .     147 

Irido-cyclitis       -                          ...  --219 

Iritis     -  -    216 

Joints  :  opsonic  index  in  diagnosis  of  tuberculous  joints  -  -       83 

tuberculous      -  83,  139 

Keratitis  :  opsonic  index  in  diagnosis  of  tuberculous  keratitis  -  84,  216 

Kidney  :  opsonic  index  in  diagnosis  of  tuberculous  kidney       -  -       83 

Lactic  acid  bacilli  injections  in  urethritis           ....  177 

Laryngitis  :  opsonic  index  in  diagnosis  of  tuberculous  laryngitis          -  83 

Lupus    -             ---                           ....  142 

,,     mixed  infection                -                                                       -             -  144 

,,     opsonic  index  in  diagnosis                                                  -             -  84 

Malta  fever       -  -  206 

Media  for  growths  for  estimation  of  opsonic  index        -  -  33 

,,      for  growths  for  vaccines  -             -  47 

Meibomians       -                         -  -                         -  225 

Meningitis  :  diagnosis  by  opsonic  index  -  84 

„            vaccine  treatment  -  210 

Meningococcus  :  differentiation  -             -             -  58 

„              emulsion  for  opsonic  index     -  -  227 

,,               preparation  of  vaccine  -             -  57 


240  INDEX 

PAGES 

Micrococcus  catarrhalis  -     184 

„                  „           differentiation               ...  56, 58 

,,                  „           effect  of  vaccine  on  opsonic  index         -             -       19 

,,                  ,,           emulsion  for  opsonic  index  -                          -       33 

„                  „           preparation  of  vaccine  -       56 

„                  ,,           vaccine  in  nasal  catarrh  -     186 

„                  ,,           vaccine  in  tracheal  catarrh  -                          -     190 

Micrococcus  melitensis  -     206 

„                   „         emulsion  for  opsonic  index  -             -             -     227 

Micrococcus  neoformans  -     209 

Mixed  infection  in  tuberculosis  -     133 

Morax-Axenfeld  bacillus  :  emulsion  for  opsonic  index  -  -             -       33 

„          „              ,,          preparation  of  vaccine  -       57 

Nasal  catarrh    -  -     184 

Negative  phase  -  20,  86 

„         „         with  tuberculin  in  tuberculosis  118,121 

Ocular  tuberculosis         -  ....     149 

,,           „           diagnosis      -  -     215 

„           „           treatment    -  -     218 

„           „           use  of  mixed  tuberculins     -  -     116 

Ophthalmo-reaction  (Calmette)  102,  215 

Opsonic  index  :  accuracy  of  method    -  -       39 

„             ,,       as  a  guide  to  diagnosis  -       81 

„             „       as  a  guide  to  immunization     -  92,  126 

„             „       as  an  aid  to  prognosis  -       89 

,,             ,,       effect  of  exercise  in  tuberculosis  -       75 

,,             ,,        effect  of  menstruation  81,  87 

effect  upon  by  T.R.'s  of  each  type  -                          -     232 

,,             ,,       hsemophagocytic  index  -       43 

„             ,,        in  acute  and  chronic  diseases  -  -       80 

„             „        in  cured  sanatorium  cases       -  82,  136 

„             ,,       in  disease        -  -       74 

„       in  eye  diseases  -  214,  216,  218 

„             „       in  gonococcal  infections  -  172,  178,  182 

„             „        in  health          -  -       71 

„             ,,        in  infancy        -  -       73 

,,             „        in  pneumonia  168,  169 

„             ,,        in  scarlet  fever  -     165 

„             „        in  the  insane    -  -       80 

,,             ,,       in  vaccine  treatment  of  catarrh  -     188 

,,  „       in  vaccine  treatment  of  cerebro-spinal  meningitis      -     211 

„             „        method  of  determination        -  29,  227 

,,             ,,       methods  of  raising       -  26 

„             „       method  of  determination         -  29, 227 

„             „       relationship  of  infection  to     -  -             -             -       17 

„             ,,       special  methods  in  diagnosis  -  85,  104 

„             „       to  Bacillus  typhosus  and  Bacillus  dysenterice  •  -    228 

„             „       to  Streptococcus  rheumaticus    -  •                         -     164 


INDEX  241 

PAGES 

Opsonic  index  :    value  in  acute  febrile  conditions  -  94 

„             ,,       value  in  localized  infections    -  93 

,,             ,,       value  in  treatment  of  tuberculosis       -  118,127 

Opsonins  :  demonstration  of  presence  -  5 

,,           fate  in  the  organism  -  16 

,,          nature  and  constitution      -  -  6 

,,           site  of  formation    -  -  15 

Osteo-myelitis     -  -  154 

,,         ,,         use  of  stock  vaccine  in    -  -  46 

Ovary  :  opsonic  index  in  diagnosis  of  tuberculous  ovary  -  84 

Percentage  index  (Simon)  -  42 

Periostitis           -             •             -             -             -             -  -             -154 

Peritonitis  :  diagnosis  of  tuberculous  peritonitis  by  opsonic  index       -  83 

,,             tuberculous  -             -  147 

Phagocytic  index  -  43 

„              ,,      in  anti-typhoid  immunization  -  200 

Phlyctenular  keratitis    -  -  225 

Phlyctenules       -  -  216 

Phthisis.     See  Pulmonary  tuberculosis. 

Pleurisy  :  diagnosis  of  tuberculous  pleurisy  by  opsonic  index  -             -  83 

Pneumococcus  -            -  167 

,,             in  metritis  and  pyosalpinx         -  -             -  171 

,,             medium  for  growth        -  -  47 

,,             preparation  of  vaccine   -  -  52 

,,             use  of  stock  vaccine       -  -  47 

,,             vaccine  in  corneal  ulcer  -  223 

,,             vaccine  in  peritonitis    -  -  171 

,,             vaccine  in  pneumonia    -  -  167 

Pneumonia         -  -  167 

Positive  phase  20,  86 

,,         ,,         in  tuberculin  therapy    -  -  121 

Positive  phase  plateau   -             -  20 

Prognosis  :  opsonic  index  as  an  aid  to  -  89 

Puerperal  fever  :  streptococcal  -  157 

Pulmonary  tuberculosis  :  duration  of  negative  phase   -  22 

„                    ,,             effect  of  exercise  on  opsonic  index  -             -  75 

,,                      ,,             mixed  infection  in    -  -  133 

,,                     ,,             opsonic  index  as  an  aid  to  prognosis  -             -  89 

,,                     ,,             results  of  vaccine  therapy  guided  by  clinical 

symptoms                             -  -  131 

„                     ,,             results  of  vaccine  therapy  guided  by  opsonic 

methods    -  -  133 

use  of  bovine  T.R.     -  -  127 

„                     ,,             use  of  mixed  tuberculins       -  -          116,127 

,,                      „             vaccine  treatment     -  -  118 

Pyaemia  :  staphylococcal  -  155 

,,         streptococcal  -  159 

Rheumatism  :  Streptococcus  rheumaticus  -  164 

16 


242  IKDEX 

PAGES 

Snlpingitis  :  opsonic  index  in  diagnosis  of  tuberculous  -       84 

Scarlet  fever       -            -  -165 

Septicaemia  :  staphylococcal      -  -     155 

,,             streptococcal       -  -  159,  160,  161 

,,             streptococcal,  dosage  in  -  -     162 

Septus.     See  Bacillus  septu-s. 

Simon's  percentage  index         -  -       42 

Sinus  -  -  -  ....--28 

„      in  tuberculous  adenitis  -     139 

Spengler's  method  of  therapy  in  tuberculosis  -  -     114 

P.T.O.  -     124 

'Splitter'  -     112 

Staining  :  blood-films  for  opsonic  count  -       37 

Standardization  of  vaccines       -  59 

Staphylococcus  albus  vaccine  -       49 

„              aureus  in  septicaemia    -  -     155 

,,             aureus  vaccine  -       49 

„             emulsion            -  -       33 

,,             vaccine  in  acne  -     151 

„              vaccine  in  furunculosis  -     153 

Sterilization  of  vaccines             -  -       62 

Stock  vaccines  :  advisability  of  using    -  -       45 

Streptococcus     -             -  -     158 

„             classification        -  -     157 

,,             emulsion  -       33 

„             in  dacryocystitis  -     225 

,,             in  scarlet  fever    -  -     165 

,,             in  septicaemia      -  -     159 

,.             preparation  of  vaccine  -  -             -       49 

,,             rheumaticus  -     164 

Streptothrix  :  vaccine  treatment  -     212 

Sycosis  -     154 

Synovitis  of  knee  -     140 

Tabes    -  -     207 

Technique  of  opsonic  index        -  29,  227 

Temperature  :  as  a  guide  in  tuberculin  therapy  121,  135 

Toxaemia  in  tuberculosis  -     117 

Toxin  :  toxins  and  antitoxins  in  human  and  bovine  tubercle   -  -     115 

Tracheal  catarrh                                                                   •  185,  190 

Tubercle  bacillus:  differentiation  of  human  and  bovine  types  -  107,  108 

„              ,,         emulsion     -  34,  227 

human  and  bovine  types     -  -         96,  105,  110,  230 

„              „         medium  for  growth  -       47 

„              „         methods  for  isolation  48, 229 

,,              „         special  methods  for  detection  -     226 

,,               ,,         special  staining  methods     -  -     230 

splitter         -  -     231 

Tuberculin         •                          -             -            -            -  -             -     117 


INDEX  243 

PACKS 

Tuberculin  bacilliary  emulsion  -     117 

B.E.  -     125 

,,           Calmette's  ophthalmo-reaction       -  102, 215 

,,           choice  of     -  -     113 

Denys'         -  - 117,  123,  130 

dosage  -  23,  25,  118,  122,  127 

dosage  without  guidance  of  opsonic  index  -  -     128 

,,           in  bones  and  joints  -     139 

,,            in  cured  sanatorium  cases   -  -     136 

,,            in  genito-urinary  tuberculosis        -  -     145 

,,           in  eye  diseases        -  -     218 

,,            in  tuberculous  adenitis       -  -     138 

,,           intervals  in  administration  128,  130 

,,            method  of  making  special    -  -       47 

,,           negative  phase  with  -     118 

newT.R.  (Koch)  63,  117 

P.B.E.          -  125 

,,           preparation  of         -  63 

P.T.O.  -     124 

P.T.R.          -  125 

„            purified  old  tuberculin        -  -     117 

,,           results  in  phthisis  with  opsonic  index  -     131 

,,           results  in  phthisis  without  opsonic  index    -  -     133 

Spengler's  P.T.O.    -  -     124 

„           special  :  difficulty  of  making  -       45 

T.A.  old  tuberculin  117,  122 

T.O.  (human)  63,  124 

T.R.  -     125 

,,  use  in  diagnosis      -  -      86,  99,  104 

,,  use  of  mixed  human  and  bovine     -  -  116,  130,  218 

,,           Von  Pirquet's  cutaneous  reaction   -  -     102 

Tuberculosis  :  aetiology  -       96 

eye  -  116,  149,  215 

,,             genito-urinary    -  -     145 

,,             graduated  exercise  in  treatment  of  -     128 

,,             intestinal  -     147 

localized  137,  142 

„             methods  of  diagnosis      -  -       99 

,,  of  lungs.     See  Pulmonary  tuberculosis. 

„             opsonic  index  as  an  aid  to  prognosis        -  -       90 

,,             opsonic  index  in  -       74 

,,             secondary  infections       -  -     128 

,,             treatment  under  guidance  of  clinical  symptoms  -     122 

treatment  with  vaccines  120,  129 

,,             types — human  and  bovine  -     111 

Tuberculous  meningitis  -     148 

„           peritonitis  -     147 

Tubing  vaccines  -       62 

Typhoid  carriers  -     201 

,,         group  of  bacilli  -     19(> 

16—2 


244  INDEX 

PAGES 

Typhoid,  immunization  against  -     198 

,,         specific  therapy  in      -  -     202 

types  of  196,  197 

Ulcers  :  tuberculous  -  144 

„  corneal  -  223 

Urethritis  -  172,  173,  175 

,,  differential  diagnosis  by  opsonic  index  -  -  84,  175,  170 

„  treatment  with  Bacillus  coli  communis  vaccine  -  195 

,,  treatment  with  lactic  acid  bacilli  -  -  177 

Vaccine  administration  -  68 

,,  by  the  mouth  -  70 

„  effect  on  opsonic  index  -  18 

„  gonococcus  stock  -  -  46 

„  preparation  of  -  45 

„  preparation  of  anti-typhoid  vaccine  -  -  199 

,,  preparation  of  combined  vaccines  -  -  66 

,,  stock :  advisability  of  45 

,,  treatment  of  tuberculosis  -  120 

Von  Pirquet  :  cutaneous  reaction  -             -     102 


H.    K.    LEWIS,    130,   (iOWER   STREET,    LONDON. 


Date  Due 


PRINTED  IN  U.S.* 


A  000  499  557  7 


QW690 
AU29v 
1908 


Allen,  Richard  W 
Vaccine  therapy. . . 


MEDICAL  SCIENCES  LIBRARY 

UNIVERSITY  OF  CALIFORNIA,  IRVINE 

IRVINE,  CALIFORNIA  92664 


